Ortho-substituted aromatic ether compounds and their use in pharmaceutical compositions for pain relief

ABSTRACT

The invention provides compounds of formula I: ##STR1## wherein A, B, D, X, R 1 , and R 3  have any of the values defined in the specification, as well as N-oxides thereof, S-oxides thereof, pharmaceutically acceptable salts thereof, and in vivo hydrolizable esters and amides thereof, that are useful to relieve pain. The invention also provides pharmaceutical compositions as well as synthetic and therapeutic methods relating to such compounds.

This application is a national stage filing under 35 U.S.C. §371 ofPCT/GB95/02030, filed Aug. 29, 1995.

This invention relates to novel, aromatic compounds andpharmaceutically-acceptable salts thereof which possess usefulpharmacological properties. More particularly the compounds of theinvention are antagonists of the pain enhancing effects of E-typeprostaglandins. The invention also relates to processes for themanufacture of the aromatic compounds and pharmaceutically-acceptablesalts thereof; to novel pharmaceutical compositions containing them; andto use of the compounds in pain relief.

The compounds of the invention are useful in the treatment of pain suchas the pain associated with joint conditions (such as rheumatoidarthritis and osteoarthritis), postoperative pain, post-partum pain, thepain associated with dental conditions (such as dental caries andgingivitis), the pain associated with burns (including sunburn), thetreatment of bone disorders (such as osteoporosis, hypercalcaemia ofmalignancy and Paget's disease), the pain associated with sportsinjuries and sprains and all other painful conditions in which E-typeprostaglandins wholly or in part play a pathophysiological role.

Non-steroidal anti-inflammatory drugs (NSAIDS) and opiates are the mainclasses of drugs in pain relief. However both possess undesireable sideeffects. NSAIDS are known to cause gastrointestinal irritation andopiates are known to be addictive.

We have now found a class of compounds structurally different to NSAIDSand opiates, and useful in relief of pain.

The compounds of the invention may also possess anti-inflammatory,anti-pyretic and anti-diarrhoeal properties and be effective in otherconditions in which prostaglandin E₂ (PGE₂) wholly or in part plays apathophysiological role.

According to the invention there is provided a compound of the formulaI; ##STR2## wherein:

A is an optionally substituted: 8- to 10-membered bicyclic heteroaryl,5- or 6-membered heteroaryl, naphthyl or phenyl; provided that the--OCH(R³)- and -X- linking groups are positioned in a 1,2 relationshipto one another on ring carbon atoms;

B is an optionally substituted 5- or 6-membered heteroaryl ring systemor optionally substituted phenyl;

D is optionally substituted: pyridyl, pyrazinyl, pyrimidinyl,pyridazinyl, pyrrolyl, thienyl, furyl, pyrazolyl, thiazolyl,isothiazolyl, oxazolyl, isoxazolyl or phenyl;

X is of the formula --(CHR⁴)_(n) --or--(CHR⁴)_(p) CR⁴ ═CR⁴ (CHR⁴)_(q)--wherein n is 1 to 3 and p and q are either both 0 or one of p and q is1 and the other is 0;

R¹ is positioned on ring B in a 1,3 or 1,4 relationship with the--OCH(R³)-- linking group in 6-membered rings and in a 1,3 relationshipwith the --OCH(R3)-- linking group in 5-membered rings and is carboxy,carboxyC₁₋₃ alkyl, tetrazolyl, tetrazolylC₁₋₃ alkyl, tetronic acid,hydroxamic acid, sulphonic acid, or R¹ is of the formula --CONR^(a)R^(a1) wherein R^(a) is hydrogen or C₁₋₆ alkyl and R^(a1) is hydrogen oroptionally substituted; C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇cycloalkyl, C₃₋₇ cycloalkylC₁₋₆ alkyl, C₃₋₇ cycloalkylC₂₋₆ alkenyl, C₃₋₇cycloalkylC₂₋₆ alkynyl, C₅₋₇ cycloalkenyl, C₃₋₇ cycloalkenylC₁₋₆ alkyl,C₅₋₇ cycloalkenylC₂₋₆ alkenyl, C₅₋₇ cycloalkenylC₂₋₆ alkynyl, C₁₋₃ alkylsubstituted by a 5- or 6-membered saturated or partially saturatedheterocyclic ring, 5- or 6-membered heteroaryl C₁₋₃ alkyl, 5- or6-membered saturated or partially saturated heterocyclic ring, or 5- or6-membered heteroaryl; or wherein R^(a) and R^(a1) together with theamide nitrogen to which they are attached (NR^(a) R^(a1)) form an aminoacid residue or ester thereof; or R¹ is of the formula --CONHSO₂ R^(b)wherein R^(b) is optionally substituted: C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₇ cycloalkyl, C₃₋₇ cycloalkylC₁₋₆ alkyl, C₃₋₇ cycloalkylC₂₋₆alkenyl, C₃₋₇ cycloalkylC₂₋₆ alkynyl, C₅₋₇ cycloalkenyl, C₅₋₇cycloalkenylC₁₋₆ alkyl, C₅₋₇ cycloalkenylC₂₋₆ alkenyl, C₅₋₇cycloalkenylC₂₋₆ alkynyl, 5- or 6-membered heteroaryl, 5- or 6-memberedheteroarylC₁₋₆ alkyl, phenyl, phenylC₁₋₆ alkyl, 5- or 6-memberedsaturated or partially saturated heterocyclyl or 5- or 6-memberedsaturated or partially saturated heterocyclylC₁₋₆ alkyl;

R³ is hydrogen or C₁₋₄ alkyl;

R⁴ is hydrogen or C₁₋₄ alkyl;

and N-oxides thereof where chemically possible;

and S-oxides of sulphur containing rings where chemically possible;

and pharmaceutically acceptable salts and in vivo hydrolysable estersand amides thereof;

excluding 4-(2-benzyl-3-hydroxy-4-formylphenoxymethyl)-3-methoxybenzoicacid and 4-(2-(3-phenylprop-2-en-1-yl)-3-hydroxy 4-formylphenoxymethyl)-3-methoxybenzoic acid.

An 8 to 10 membered bicyclic heteroaryl ring system is a bicyclic arylring system having from 8 to 10 ring atoms wherein 1, 2, 3, 4 or 5 ofthe ring atoms are selected from nitrogen, oxygen and sulphur.

A 5- or 6-membered heteroaryl ring system is a monocyclic aryl ringsystem having 5 or 6 ring atoms wherein 1, 2 or 3 ring atoms areselected from nitrogen, oxygen and sulphur.

A 5- or 6-membered saturated or partially saturated heterocyclic ring isa ring system having 5 or 6 ring atoms wherein 1, 2 or 3 of the ringatoms are selected from nitrogen, oxygen and sulphur.

Particular 8 to 10 membered bicyclic heteroaryl ring systems includebenzofuryl, indolizinyl, isoindolyl, indolyl, indazolyl, benzothienyl,quinolyl, isoquinolyl, quinoxalinyl, quinazolinyl, cinnolinyl andphthalazinyl.

Particular 5- or 6-membered heteroaryl rings include pyrrolyl,imidazolyl, pyrazolyl, isothiazolyl, isoxazolyl, pyridyl, pyrazinyl,pyrimidinyl, pyridazinyl, thiazolyl, thiadiazolyl, thienyl, furyl andoxazolyl.

Particular 5- or 6-membered saturated or partially saturatedheterocyclic ring ring systems include pyrrolidinyl, pyrrolinyl,imidazolidinyl, pyrazolidinyl, piperidyl, piperazinyl and morpholinyl.

Particular substituents for ring carbon atoms in A include halo,trifluoromethyl, nitro, hydroxy, amino, C₁₋₄ alkylamino, diC₁₋₄alkylamino, cyano, C₁₋₆ alkoxy, C₁₋₆ alkylS(O)_(p) --(p is 0, 1 or 2),phenyls(O)_(p) --(p is 0, 1 or 2), C₁₋₆ alkyl (optionally substituted byhydroxy, amino, halo, nitro, C₁₋₄ alkylS(O)_(p) --(p is 0, 1 or 2), C₁₋₄alkoxy, phenylS (O)_(p) --(p is 0, 1 or 2) or cyano), carbamoyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, C₃₋₇ cycloalkylC₁₋₃ alkyl, C₃₋₇cycloalkylC₂₋₃ alkenyl, C₃₋₇ cycloalkylC₂₋₃ alkynyl, C₁₋₄alkoxycarbonylamino, C₁₋₄ alkanoylamino, C₁₋₄ alkanoyl(N-C₁₋₄alkyl)amino, C₁₋₄ alkanesulphonamido, benzenesulphonamido,aminosulphonyl, C₁₋₄ alkylaminosulphonyl, di(C₁₋₄ alkyl)aminosulphonyl,C₁₋₄ alkoxycarbonyl, C₂₋₄ alkanoyloxy, C₁₋₆ alkanoyl, formylC₁₋₄ alkyl,trifluoroC₁₋₃ alkylsulphonyl, hydroxyiminoC₁₋₆ alkyl, C₁₋₄alkoxyiminoC₁₋₆ alkyl, C₁₋₆ alkylcarbamoylamino, phenyl, C₁₋₄alkylcarbamoyl and di(C₁₋₄ alkyl)carbamoyl.

Particular substituents for ring carbon atoms in B include halo,trifluoromethyl, nitro, hydroxy, C₁₋₆ alkoxy, C₁₋₆ alkyl, C₃₋₇cycloalkyl, C₃₋₇ cycloalkylC₁₋₃ alkyl, amino, C₁₋₄ alkylamino, di(C₁₋₄alkyl)amino, cyano, --S(O)pC₁₋₆ alkyl (p is 0, 1 or 2), carbamoyl, C₁₋₄alkylcarbamoyl and di(C₁₋₄ alkyl)carbamoyl.

Particular substituents for D include halo, trifluoromethyl, nitro,hydroxy, amino, C₁₋₄ alkylamino, di(C₁₋₄ alkyl)amino, cyano, C₁₋₆alkoxy, --S(O)_(p) C₁₋₄ alkyl, --S(O) phenyl (p is 0, 1 or 2), C₁₋₄alkanoyl and C₁₋₄ alkyl optionally substituted by hydroxy, halo, nitro,cyano or amino.

Particular substituents for ring carbon atoms in phenyl, heteroaryl and5- and 6-membered saturated or partially saturated heterocyclyl groupsin R^(a1) and R^(b) include halo, trifluoromethyl, nitro, hydroxy,amino, C₁₋₄ alkylamino, diC₁₋₄ alkylamino, cyano, C₁₋₆ alkoxy, carboxy,C₁₋₆ alkylS(O)_(p) --(p is 0, 1 or 2), phenylS(O)_(p) --(p is 0, 1 or2), C₁₋₆ alkyl (optionally substituted by hydroxy, amino; halo, nitro,C₁₋₄ alkylS(O)_(p) --(p is 0, 1 or 2), C₁₋₄ alkoxy, phenylS(O)_(p) --(pis 0, 1 or 2) or cyano), carbamoyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇cycloalkyl, C₃₋₇ cycloalkylC₁₋₃ alkyl, C₃₋₇ cycloalkylC₂₋₃ alkenyl, C₃₋₇cycloalkylC₂₋₃ alkynyl, C₁₋₄ alkoxycarbonylamino, C₁₋₄ alkanoylamino,C₁₋₄ alkanoyl(N-C₁₋₄ alkyl)amino, C₁₋₄ alkanesulphonamido,benzenesulphonamido, aminosulphonyl, C₁₋₄ alkylaminosulphonyl, di(C₁₋₄alkyl)aminosulphonyl, C₁₋₄ alkoxycarbonyl, C₂₋₄ alkanoyloxy, C₁₋₆alkanoyl, formylC₁₋₄ alkyl, trifluoroC₁₋₃ alkylsulphonyl,hydroxyiminoC₁₋₆ alkyl, C₁₋₄ alkoxyiminoC₁₋₆ alkyl, C₁₋₆alkylcarbamoylamino, phenyl, C₁₋₄ alkylcarbamoyl and di(C₁₋₄alkyl)carbamoyl.

Where a ring nitrogen atom in A or B can be substituted without becomingquaternised, it can be unsubstituted or substituted by C₁₋₄ alkyl.

The term `alkyl` when used herein includes straight chain and branchedchain substituents for example methyl, ethyl, n-propyl, isopropyl,n-butyl and isobutyl. The same convention applies to other radicals, forexample hydroxyiminoC₁₋₄ alkyl includes 1-(hydroximino)ethyl and2-(hydroxyimino)ethyl.

Amino acid residues formed from R^(a) and R^(a1) together with the amidenitrogen to which they are attached and esters thereof include forexample radicals of the formula --NH--CH(R^(c))--COOR^(d) wherein R^(c)is hydrogen, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, phenyl, phenylC₁₋₃alkyl, 5- or 6-membered heteroaryl or 5- or 6-membered heteroarylC₁₋₃alkyl and R^(d) is hydrogen or C₁₋₆ alkyl, wherein alkyl, alkenyl,alkynyl, phenyl and heteroaryl groups are optionally substituted.Examples of substituents include those mentioned above for ring A; inparticular hydroxy.

It will be appreciated that when an alkenyl or alkynyl group is directlylinked to the nitrogen of a primary or secondary amine, the double ortriple bond may not be in the 1-position. Similarly alkyl groups whichare substituted by halo, hydroxy or an amine may not be substituted bythese substituents in the 1-position when the alkyl group is directlylinked to the nitrogen of a primary or secondary amine.

Examples of C₁₋₆ alkoxycarbonyl are methoxycarbonyl, ethoxycarbonyl andt-butoxycarbonyl; examples of carboxyC₁₋₃ alkyl are carboxymethyl,2-carboxyethyl, 1-carboxyethyl and 3-carboxypropyl; examples of C₁₋₆alkoxycarbonylC₁₋₃ alkyl are methoxycarbonylmethyl, ethoxycarbonylmethyland methoxycarbonylethyl; examples of tetrazolylC₁₋₃ alkyl aretetrazolylmethyl and 2-tetrazolylethyl; examples of C₁₋₄ alkoxy aremethoxy, ethoxy, propoxy and isopropoxy; examples of C₂₋₆ alkenyl arevinyl and allyl; examples of C₂₋₆ alkynyl are ethynyl and propynyl;examples of C₃₋₇ cycloalkyl are cyclopropyl, cyclobutyl and cyclohexyl;examples of C₃₋₇ cycloalkylC₁₋₃ alkyl are cyclopropylmethyl andcyclohexylmethyl; examples of C₃₋₇ cycloalkylC₂₋₃ alkenyl arecyclopropylethenyl and cyclopentylpropenyl; examples of C₃₋₇cycloalkylC₂₋₃ alkynyl are cyclopropylethynyl and cyclopentylethynyl;examples of C₅₋₇ alkenyl are cyclopentenyl and cyclohexenyl; examples ofC₅₋₇ cycloalkenylC₁₋₃ alkyl are cyclopentenylmethyl andcyclohexenylmethyl; examples of C₅₋₇ cycloalkenylC₂₋₃ alkenyl arecyclohexenylethenyl and cycloheptenylethenyl; examples of C₅₋₇cycloalkenylC₂₋₃ alkynyl are cyclopentenylethynyl andcyclohexenylethynyl; examples of C₁₋₄ alkanoyl are formyl, acetyl,propionyl and butyryl; examples of halo are fluoro, chloro, bromo andiodo; examples of C₁₋₄ alkylamino are methylamino, ethylamino,propylamino and isopropylamino; examples of di(C₁₋₄ alkyl)amino aredimethylamino, diethylamino and ethylmethylamino; examples of --S(O)_(p)C₁₋₄ alkyl are methylthio, methylsulphinyl and methylsulphonyl; examplesof C₁₋₄ alkylcarbamoyl are methylcarbamoyl and ethylcarbamoyl; examplesof di(C₁₋₄ alkyl)carbamoyl are dimethylcarbamoyl, diethylcarbamoyl andethylmethylcarbamoyl; examples of C₁₋₆ alkyl are methyl, ethyl, propyland isopropyl; examples of C₁₋₄ alkoxycarbonylamino aremethoxycarbonylamino and ethoxycarbonylamino; examples of C₁₋₄alkanoylamino are acetamido and propionamido; examples of C₁₋₄alkanoyl(N-C₁₋₄ alkyl)amino are N-methylacetamido andN-methylpropionamido; examples of C₁₋₄ alkanesulphonamido aremethanesulphonamido and ethanesulphonamido; examples of C₁₋₄alkylaminosulphonyl are methylaminosulphonyl and ethylaminosulphonyl;examples of di(C₁₋₄ alkyl)aminosulphonyl are dimethylaminosulphonyl,diethylaminosulphonyl and ethylmethylaminosulphonyl; examples of C₂₋₄alkanoyloxy are acetyloxy and propionyloxy; examples of formylC₁₋₄ alkylare formylmethyl and 2-formylethyl; examples of hydroxyiminoC₁₋₆ alkylare hydroxyiminomethyl, 1-(hydroxyimino)ethyl and 2-(hydroxyimino)ethyland examples of C₁₋₄ alkoxyiminoC₁₋₆ alkyl are methoxyiminomethyl,ethoxyiminomethyl and 2-(methoxyimino)ethyl.

Preferably A is optionally substituted: phenyl, pyridyl, pyrimidyl,pyrazinyl, pyridazinyl, thienyl, 1,2,3-thiadiazolyl, oxazolyl, naphthylor of the formula: ##STR3## wherein E is nitrogen or CH, F is nitrogenor CH, G is sulphur or oxygen and I is nitrogen or CH₃.

Preferably B is optionally substituted: phenyl, pyridyl, thiazolyl,thienyl, thiadiazolyl, pyrazinyl, pyridazinyl, pyrimidyl, oxazolyl orimidazolyl.

Preferably D is optionally substituted: thienyl or phenyl.

More preferably A is optionally substituted: phenyl, pyridyl, pyrimidyl,pyrazinyl, pyridazinyl, thienyl or 1,2, 3-thiadiazolyl.

More preferably B is optionally substituted: phenyl, pyridyl, thiazolyl,thienyl, thiadiazolyl, pyrazinyl, pyridazinyl or pyrimidyl.

More Preferably D is optionally substituted phenyl.

Yet more preferably A is optionally substituted: phenyl, pyridyl,thienyl or pyrimidyl.

Yet more preferably B is optionally substituted: pyridyl, phenyl,thiazolyl, thienyl or pyridazinyl.

Most preferably A is optionally substituted: phenyl or thienyl.

Most preferably B is optionally substituted phenyl, thiazolyl orpyridyl.

In particular A is optionally substituted phenyl.

In particular B is phenyl.

Preferred optional substituents for ring carbon atoms in A, are halo,nitro, trifluoromethyl, cyano, hydroxy, amino, C₁₋₆ alkoxy, C₁₋₄alkanoylamino, C₁₋₄ alkylS(O)p--, C₁₋₆ alkyl (optionally substituted bycyano, phenylS(O)p-- or C₁₋₄ alkylS(O)p--), C₁₋₄ alkanesulphonamido,benzenesulphonamido, C₁₋₆ alkanoyl, phenyl, C₁₋₄ alkoxyiminoC₁₋₄ alkyland hydroxyiminoC₁₋₄ alkyl.

More preferably optional substituents for ring carbon atoms in A includefluoro, chloro, bromo, nitro, trifluoromethyl, cyano, amino, methoxy,methyl, isopropyl, hexyl, methylthio, benzensulphonyl, phenyl, acetyl,formyl, benzenesulphonamido, hydroxyiminomethyl, 1-(hydroxyimino)ethyl,cyanomethyl and benzensulphonylmethyl.

Preferably, when A is a 6-membered ring, it is unsubstituted, orsubstituted in the 4, 5 or 6-position (when the ring is numbered suchthat the ring carbon bearing the --OCH(R³) -- group is in the 1-positionand the ring carbon bearing the --X--D group is in the 2-position).

More preferably, when A is a 6-membered ring, A is unsubstituted, orsubstituted in the 4 or 6-position using the above numbering system.Most preferably, when A is a 6-membered ring, A is unsubstituted, orsubstituted in the 4-position using the above numbering system.

A preferred optional substituent for ring carbon atoms in B is hydroxy.

Preferably the aryl group in --X--D is unsubstituted or substituted byone or two substituents.

Preferably, optional substituents for the aryl group in --X--D areselected from halo, nitro, hydroxy, cyano, C₁₋₄ alkyl, amino, C₁₋₄alkoxy and carbamoyl.

Most preferably the aryl group in --X--D is unsubstituted.

Preferably A is unsubstituted or substituted by one or two substituents.

Preferably B is unsubstituted or substituted by one substituent.

Preferably R¹ is carboxy, tetrazolyl or of the formula --CONHR^(a1) or--CONHSO₂ R^(b).

Preferably R^(a) is optionally substituted: C₁₋₆ alkyl, tetrazolyl orpyridylC₁₋₃ alkyl.

Preferably R^(b) is C₁₋₄ alkyl (optionally substituted by hydroxy,nitro, cyano, amino, C₁₋₄ alkylamino, di-C₁₋₄ alkylamino, C₁₋₄alkanoylamino, C₁₋₄ alkyl-N-C₁₋₄ alkanoylamino, carbamoyl, C₁₋₄alkylcarbamoyl, di-C₁₋₄ alkanoylcarbamoyl, halo, C₁₋₄ alkoxy) oroptionally substituted: phenylC₁₋₃ alkyl, pyridylC₁₋₃ alkyl, phenyl,thienyl, thiadiazolyl, oxazolyl, isoxazolyl, pyrazolyl or1,1-dioxidotetrahydrothienyl.

Most preferably R^(b) is C₁₋₄ alkyl, hydroxyC₁₋₄ alkyl, C₁₋₄ alkoxyC₁₋₄alkyl, phenyl (optionally substituted by halo, cyano, nitro, carbamoyl,C₁₋₄ alkylcarbamoyl, di-C₁₋₄ alkylcarbamoyl, hydroxy, amino, C₁₋₄alkanoylamino, N-C₁₋₄ alkanoyl-N-C₁₋₄ alkylamino, C₁₋₄ alkylamino ordi-(C₁₋₄ alkyl)amino), benzyl (optionally substituted by halo, cyano,nitro, carbamoyl, C₁₋₄ alkylcarbamoyl, di-C₁₋₄ alkylcarbamoyl, hydroxy,amino, C₁₋₄ alkanoylamino, N-C₁₋₄ alkanoyl-N-C₁₋₄ alkylamino, C₁₋₄alkylamino or di-(C₁₋₄ alkyl)amino), thiadiazolyl (optionallysubstituted by C₁₋₄ alkanoylamino, amino, C₁₋₄ alkylamino or di-C₁₋₄alkylamino), thienyl (optionally substituted by halo or pyridyl),isoxazolyl (optionally substituted by C₁₋₄ alkyl or halo), pyrazolyl(optionally substituted by C₁₋₄ alkyl or halo) or1,1-dioxidotetrahydro-2-thienyl.

More preferably R¹ is carboxy or tetrazolyl or R¹ is of the formula--CONHR^(a1) wherein R^(a1) is tetrazolyl, pyridylC₁₋₃ alkyl or C₁₋₆alkyl (optionally substituted by hydroxy, amino, cyano or C₂₋₄alkanoyloxy), or R¹ is of the formula --CONHSO₂ R^(b) wherein R^(b) isC₁₋₆ alkyl or phenyl (wherein the alkyl and the phenyl group areoptionally substituted by hydroxy, halo, cyano, C₁₋₄ alkyl, nitro,amino, carbamoyl, C₁₋₄ alkoxy, or C₁₋₄ alkyls(O)p--(p is 0, 1 or 2)).

Most preferably, R¹ is carboxy, tetrazolyl or of the formula --CONHR^(a)wherein R^(a) is tetrazolyl, pyridylmethyl or C₁₋₆ alkyl (optionallysubstituted by hydroxy or cyano), or R¹ is of the formula --CONHSO₂R^(b) wherein R^(b) is C₁₋₆ alkyl or phenyl (wherein the alkyl andphenyl group are optionally substituted by hydroxy, halo, cyano or C₁₋₄alkyl).

In a particular aspect R¹ is carboxy, carboxyC₁₋₃ alkyl, tetrazolyl,tetrazolylC₁₋₃ alkyl, tetronic acid, hydroxamic acid, sulphonic acid, orR¹ is of the formula --CONR^(a) R^(a1) wherein R^(a) is hydrogen or C₁₋₆alkyl and R^(a1) is hydrogen, C₁₋₆ alkyl (optionally substituted byhalo, hydroxy, nitro, cyano, trifluoromethyl, C₁₋₄ alkoxy or C₁₋₄alkoxycarbonyl), C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₃ alkyl substituted by a5- or 6-membered saturated or partially saturated heterocyclic ring, 5-or 6-membered heteroaryl C₁₋₃ alkyl, 5- or 6-membered saturated orpartially saturated heterocyclic ring, or 5- or 6-membered heteroaryl orR¹ is of the formula --CONHSO₂ R^(b) wherein R^(b) is hydrogen, C₁₋₆alkyl (optionally substituted by halo, hydroxy, nitro, cyano,trifluoromethyl, C₁₋₄ alkoxy or C₁₋₄ alkoxycarbonyl), C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₃ alkyl substituted by a 5- or 6-membered saturated orpartially saturated heterocyclic ring, 5- or 6-membered heteroarylC₁₋₃alkyl phenylC₁₋₃ alkyl, 5- or 6-membered saturated or partiallysaturated heterocyclic ring, 5- or 6-membered heteroaryl or phenyl;wherein any saturated or partially saturated heterocyclic ring orheteroaryl group in R^(a1) is optionally substituted by halo, hydroxy,nitro, cyano, trifluoromethyl, C₁₋₄ alkoxy or C₁₋₄ alkoxycarbonyl andany phenyl, saturated or partially saturated heterocyclic ring andheteroaryl group in R^(b) is optionally substituted.

Preferably X is of the formula --CR⁴ ═CR⁴ or --CH(R⁴)--CH(R⁴)--.

Most preferably X is of the formula --CH═CH-- or --CH₂ --CH₂ --.

In particular X is of the formula --CH₂ --CH₂ --.

Preferably R³ is hydrogen or methyl.

Most preferably R³ is hydrogen.

Preferably R⁴ is hydrogen or methyl.

Most preferably R⁴ is hydrogen.

A preferred class of compounds is that of the formula (V): ##STR4##wherein

R¹ and R³ are as hereinabove defined, R⁶ is hydrogen, halo,trifluoromethyl, nitro, hydroxy, amino, cyano, C₁₋₆ alkoxy, C₁₋₆alkylS(O)_(p) (p is 0, 1 or 2), phenyls(O)_(p) (p is 0, 1 or 2), C₁₋₆alkyl (optionally substituted by hydroxy, amino, halo, nitro or cyano),C₃₋₇ cycloalkyl, C₃₋₇ cycloalkylC₁₋₃ alkyl, carbamoyl, C₁₋₄alkylcarbamoyl, di(C₁₋₄ alkyl)carbamoyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₁₋₄ alkoxycarbonylamino, C₁₋₄ alkanoylamino, C₁₋₄ alkanoyl(N-C₁₋₄alkyl)- amino, C₁₋₄ alkanesulphonamido, benzenesulphonamido,aminosulphonyl, C₁₋₄ alkylaminosulphonyl, di(C₁₋₄ alkyl)aminosulphonyl,C₁₋₄ alkoxycarbonyl, C₂₋₄ alkanoyloxy, C₁₋₆ alkanoyl, formylC₁₋₄ alkyl,trifluoroC₁₋₃ alkylsulphonyl, hydroxyiminoC₁₋₆ alkyl, C₁₋₄alkoxyiminoC₁₋₆ alkyl or C₁₋₆ alkylcarbamoylamino, X is --(CH₂)₂ -- or--CH═CH-- and B is phenyl, thiadiazolyl or pyridyl.

Particular compounds of the present invention are:

4-[6-bromo-2-(phenethyl)phenoxymethyl]benzoic acid;

4-[5-nitro-2-(phenethyl)phenoxymethyl]benzoic acid;

4-[4-chloro-6-methyl-2-(phenethyl)phenoxymethyl]benzoic acid;

4-[5-bromo-6-cyano-2-(phenethyl)phenoxymethyl]benzoic acid;

4-[5-chloro-2-(phenethyl)phenoxymethyl]benzoic acid;

4-[4-cyanomethyl-2-(phenethyl)phenoxymethyl]benzoic acid;

4-[2-(phenethyl)phenoxymethyl]benzoic acid;

4-[6-bromo-2-(phenethyl)phenoxymethyl]-2-hydroxybenzoic acid;

4-[5-methyl-2-(phenethyl)phenoxymethyl]benzoic acid;

4-[2-(phenethyl)-6-phenylphenoxymethyl]benzoic acid;

4-[6-amino-2-(phenethyl)phenoxymethyl]benzoic acid;

4-[6-methanethio-2-(phenethyl)phenoxymethyl]benzoic acid;

4-[4-(1-(hydroxyimino)ethyl)-2-(phenethyl)phenoxymethyl]benzoic acid;

4-[4-methyl-2-(phenethyl)phenoxymethyl]benzoic acid;

4-[4-bromo-2- (phenethyl) phenoxymethyl]benzoic acid;

4-[4-methoxy-2-(phenethyl)phenoxymethyl]benzoic acid;

4-[6-cyano-2-(phenethyl)phenoxymethyl]benzoic acid;

4-[6-cyano-4-methyl-2-(phenethyl)phenoxy methyl]benzoic acid;

4-[4-chloro-2-(phenethyl)phenoxymethyl]benzoic acid;

4-[6-benzenesulphonylmethyl-2-(phenethyl)phenoxymethyl]benzoic acid;

4-[4-methanethio-2-(phenethyl)phenoxymethyl]benzoic acid;

4-[5-bromo-2-(phenethyl)phenoxymethyl]benzoic acid;

4-[6-isopropyl-2-(phenethyl)phenoxymethyl]benzoic acid;

5-[4-(2-(phenethyl)-6-phenylphenoxymethyl)phenyl]tetrazole;

5-[4-(4-hydroxy-2-(phenethyl)phenoxymethyl)phenyl]tetrazole;

5-[4-(4-methoxy-2-(phenethyl)phenoxymethyl)phenyl]tetrazole;

5-[4-(2-(phenethyl) phenoxymethyl)phenyl]tetrazole;

5-[4-(4-chloro-2-(phenethyl)phenoxymethyl)phenyl]tetrazole;

5-[4-(4-bromo-2-(phenethyl)phenoxymethyl)phenyl]tetrazole;

5-[4-(6-bromo-2-(phenethyl)phenoxymethyl)phenyl]tetrazole; and

5-[4-(6-isopropyl-2-(phenethyl)phenoxymethyl)phenyl]tetrazole andpharmaceutically acceptable salts and in vivo hydrolysable esters andamides thereof.

It is to be understood that, insofar as certain of the compounds offormula (I) defined above may exist in optically active or racemicforms, by virtue of the compounds of the formula (I) containing anasymmetric carbon atom, the invention includes in its definition ofactive ingredient any such optically active or racemic form whichpossesses anti-hyperalgesic properties. The synthesis of opticallyactive forms may be carried out by standard techniques of organicchemistry well known in the art, for example by synthesis from opticallyactive starting materials or by resolution of a racemic form. Similarly,the pain relieving effects may be evaluated using the standardlaboratory techniques referred to hereinafter.

An in vivo hydrolysable ester of a compound of the formula (I)containing carboxy group is, for example, a pharmaceutically acceptableester which is hydrolysed in the human or animal body to produce theparent acid, for example, a pharmaceutically acceptable ester formedwith a (1-6C)alcohol such as methanol, ethanol, ethylene glycol,propanol or butanol, or with a phenol or benzyl alcohol such as phenolor benzyl alcohol or a substituted phenol or benzyl alcohol wherein thesubstituent is, for example, a halo (such a s fluoro or chloro), (1-4 C)alkyl (such as methyl) or (1-4C)alkoxy (such as methoxy) group.

A suitable value for an in vivo hydrolysable amide of a compound of theformula I containing a carboxy group is, for example, a N-(1-6C)alkyl orN,N-di-(1-6C)alkyl amide such as N-methyl, N-ethyl, N-propyl,N,N-dimethyl, N-ethyl-N-methyl or N,N-diethyl amide.

A suitable pharmaceutically-acceptable salt of a compound of the formula(I) is, for example, an acid-addition salt of a compound of the formula(I) which is sufficiently basic, for example an acid-addition salt withan inorganic or organic acid such as hydrochloric, hydrobromic,sulphuric, trifluoroacetic, citric or maleic acid; or, for example asalt of a compound of the formula (I) which is sufficiently acidic, forexample an alkali or alkaline earth metal salt such as a calcium ormagnesium salt, or an ammonium salt, or a salt with an organic base suchas methylamine, dimethylamine, trimethylamine, piperidine, morpholine ortris-(2-hydroxyethyl) amine. In a further aspect the invention providesa process for preparing compounds of the formula (I) or pharmaceuticallyacceptable salts or in vivo hydrolysable amides or ester thereof, whichcomprises deprotecting a compound of the formula (VI): ##STR5## whereinR⁷ is R¹ or protected R¹ ; and R³, X, A, B and D are as hereinabovedefined, and any optional substituents are optionally protected and atleast one protecting group is present; and thereafter if necessary:

i) forming a pharmaceutically acceptable salt; and/or

ii) forming an in vivo hydrolysable ester or amide;

Protecting groups may in general be chosen from any of the groupsdescribed in the literature or known to the skilled chemist asappropriate for the protection of the group in question, and may beintroduced by conventional methods.

Protecting groups may be removed by any convenient method as describedin the literature or known to the skilled chemist as appropriate for theremoval of the protecting group in question, such methods being chosenso as to effect removal of the protecting group with minimum disturbanceof groups elsewhere in the molecule.

A suitable protecting group for a hydroxy group is, for example, anarylmethyl group (especially benzyl), a tri-(1-4C)alkylsilyl group(especially trimethylsilyl or tert-butyldimethylsilyl), anaryldi-(1-4C)alkylsilyl group (especially dimethylphenyisilyl), adiaryl-(1-4C)alkylsilyl group (especially tert-butyl-diphenylsilyl), a(1-4C)alkyl group (especially methyl), a (2-4C)alkenyl group (especiallyallyl), a (1-4C)alkoxymethyl group (especially methoxymethyl) or atetrahydropyranyl group (especially tetrahydroyran-2-yl). Thedeprotection conditions for the above protecting groups will necessarilyvary with the choice of protecting group. Thus, for example, anarylmethyl group such as a benzyl group may be removed, for example, byhydrogenation over a catalyst such as palladium-on-charcoal.Alternatively a trialkylsilyl or an aryldialkylsilyl group such as atert-butyldimethylsilyl or a dimethylphenylsilyl group may be removed,for example, by treatment with a suitable acid such as hydrochloric,sulphuric, phosphoric or trifluoroacetic acid, or with an alkali metalor ammonium fluoride such as sodium fluoride or, preferably,tetrabutylammonium fluoride. Alternatively an alkyl group may beremoved, for example, by treatment with an alkali metal (1-4C)alkylsulphide such as sodium thioethoxide or, for example, bytreatment with an alkali metal diarylphosphide such as lithiumdiphenylphosphide or, for example, by treatment with a boron oraluminium trihalide such as boron tribromide. Alternatively a (1-4C)alkoxymethyl group or tetrahydropyranyl group may be removed, forexample, by treatment with a suitable acid such as hydrochloric ortrifluoroacetic acid.

Alternatively a suitable protecting group for a hydroxy group is, forexample, an acyl group, for example a (2-4 C)alkanoyl group (especiallyacetyl) or an aroyl group (especially benzoyl). The deprotectionconditions for the above protecting groups will necessarily vary withthe choice of protecting group. Thus, for example, an acyl group such asan alkanoyl or an aroyl group may be removed, for example, by hydrolysiswith a suitable base such as an alkali metal hydroxide, for examplelithium or sodium hydroxide.

A suitable protecting group for an amino, imino or alkylamino group is,for example, an acyl group, for example a (2-4 C)alkanoyl group(especially acetyl), a (1-4 C)alkoxycarbonyl group (especiallymethoxycarbonyl, ethoxycarbonyl or tert-butoxycarbonyl), anarylmethoxycarbonyl group (especially benzyloxycarbonyl) or an aroylgroup (especially benzoyl). The deprotection conditions for the aboveprotecting groups necessarily vary with the choice of protecting group.Thus, for example, an acyl group such as an alkanoyl, alkoxycarbonyl oraroyl group may be removed for example, by hydrolysis with a suitablebase such as an alkali metal hydroxide, for example lithium or sodiumhydroxide. Alternatively an acyl group such as a tert-butoxycarbonylgroup may be removed, for example, by treatment with a suitable acidsuch as hydrochloric, sulphuric or phosphoric acid or trifluoroaceticacid, and an arylmethoxycarbonyl group such as a benzyloxycarbonyl groupmay be removed, for example, by hydrogenation over a catalyst such aspalladium-on-charcoal.

A suitable protecting group for a carboxy group is, for example, anesterifying group, for example a (1-4 C)alkyl group (especially methylor ethyl) which may be removed, for example, by hydrolysis with asuitable base such as an alkali metal hydroxide, for example lithium orsodium hydroxide; or, for example, a tert-butyl group which may beremoved, for example, by treatment with a suitable acid such ashydrochloric, sulphuric or phosphoric acid or trifluoroacetic acid.

In another aspect the compounds of the formula (I) or (VI) may beprepared:

a) from a compound of the formula (VII): ##STR6## wherein A, B, D, R³and X are as hereinabove defined and R¹⁰ is a precursor of R⁷ ;

b) when X is --(CHR⁴)_(n) -- and n is 2 or 3, by reducing a compound ofthe formula (VIII): ##STR7## wherein A, B, D, R³, R⁴, R⁷, p and q are ashereinabove defined;

c) by reacting a compound of the formula (IX) with a compound of theformula (X): ##STR8## wherein A, B, D, R³, X and R⁷ are as hereinabovedefined and L is a leaving group;

d) when A is a activated heteroaryl ring, by reacting a compound of theformula (XI) with a compound of the formula (XII): ##STR9## wherein A,B, D, X and R⁷ are as hereinabove defined; and thereafter if necessary:

i) removing any protecting groups;

ii) forming a pharmaceutically acceptable salt; and/or

iii) forming an in vivo hydrolysable ester or amide;

Particular values for R¹⁰ include cyano, carbamoyl, alkoxycarbonyl,carboxy and activated carboxy groups such as acid chlorides andactivated esters.

The cyano group may be converted into a tetrazole ring by reacting, forexample, with ammonium or tin azide in an aprotic solvent such as DMF,in a temperature range of 100° C. to 130° C. For further information ontetrazole synthesis see S. J. Wittenberger and B. J Donner JOC, 1993,58, 4139-4141; BE Huff et al, Tet. Lett, 1993, 50, 8011-8014; and J. V.Duncia et al, JOC 1991, 56, 2395-2400.

Alkoxycarbonyl may be converted into a carboxy group by acid or basehydrolysis. For example, base hydrolysis may be carried out in anorganic solvent such as methanol or THF in a temperature range ofambient to 100° C., in the presence of sodium hydroxide or potassiumhydroxide.

Acid hydrolysis may, for example, be carried out or in neat formic acidor neat trifluoroacetic acid optionally in an organic solvent such asdichloromethane.

An alkoxycarbonyl or an activated carboxy group, such as an acidchloride or activated ester, or an acyl group such as an alkanoyl groupmay be converted to an amide group by reacting with the appropriateamine in an inert solvent such as DMF or dichloromethane, in atemperature range of 0° C. to 150° C., preferably around ambienttemperature, in the presence of a base such as triethylamine.

The compounds of the formula (VII) may be prepared using processes b),c), d) or e) from the appropriate starting materials wherein R⁷ isreplaced with R¹⁰.

The compounds of the formula (VIII) may be reduced under standardconditions known in the art for the reduction of olefins, for example,catalytic hydrogenation using Raney nickel, platinum metal or its oxide,rhodium, zinc oxide, palladium-on-charcoal or Wilkinson's catalyst[RhCl(Ph₃ P)₃ as the catalyst.

Catalyst hydrogenation is conveniently carried out in the temperaturerange 0° C. to 150° C., but preferably at ambient temperature atslightly above atmospheric pressure, unless the double bond is highlysubstituted in which case higher temperatures and pressure may berequired, or Wilkinson's catalyst in which case a temperature ofapproximately 50° C. and pressure of approximately 50 atmospheres arepreferable. ##STR10## wherein A, D, R⁴, p and q are as hereinabovedefined, R¹¹ -R¹³ are independently alkyl or aryl (such as phenyl orsubstituted phenyl) L¹ is a leaving group and P is a hydroxy protectinggroup. ##STR11## wherein P, A, D, R⁴ and q are as hereinabove defined,and n is 2 or 3 and R¹⁵ is bromo or iodo. ##STR12## wherein A, D, and R⁴are as hereinabove defined and L¹¹ is a leaving group.

The compounds of the formula (XX) may be converted to compounds of theformula (VIII) by removing the hydroxy protecting group thus forming acompound of the formula (XXa), and reacting the compound of the formula(XXa) with a compound of the formula (X) in an ether forming reaction.Suitable conditions in the ether forming step are similar to thosedescribed for the reaction between compounds of the formulae (IX) and(X) below.

The compounds of the formula (XX) are conveniently prepared by reactinga compound of the formula (XXI) with a compound of the formula (XXII)(Scheme I) under conditions known for the Wittig reaction. For examplein an inert solvent such as hexane, tetrahydrofuran, or diethyl ether ina temperature range of -78° C. to ambient. Preferably R¹¹, R¹² and R¹³are all the same. In particular R¹¹ -R¹³ are all phenyl.

The compounds of the formula (XXII) are rarely isolatable and usuallyprepared in situ by deprotonating a compound of the formula (XXIII).Deprotonation is usually carried out in an inert solvent such astetrahydrofruan or diethyl ether, in a temperature range of -78° C. toambient, in the presence of a strong base. Examples of strong bases arelithium hexamethyldisilylamide (LiHMS), CH₃ SOCH₂ ⁻ Na⁺ and butyllithium.

A compound of the formula (XXIII) may be prepared by reacting a compoundof the formula (XXIV) with a compound of the formula (XXV) (scheme I).Suitable values for L¹ include halogen, such as chloro, bromo or iodo.Typically an inert solvent such as acetonitrile, diethyl ether,tetrahydrofuran or toluene is used and a temperature range of 50° C. or120° C.

Alternatively, the Horner-Emmons reaction may be used in which case thecompound of the formula (XXIII) is replaced with the appropriateHorner-Emmons reagent. This can be prepared in an analogous manner tothe Wittig reagent from a compound of the formula (XXIV) and aphosphite, for example PhCH₂ P(═O)(OEt)₂.

The Horner-Emmons reaction is conveniently carried out in an inertsolvent such as diethyl ether, THF or toluene, in a temperature range ofambient to 65° C. Examples of bases which may be used in thedeprotonation include sodium hydride, butyl lithium and LiHMS.

The compounds of the formula (XXIV) may be known or prepared fromanother compound of the formula (XXIV) or a compound of the formula(XXVI): ##STR13## wherein R⁴, D, q and optional substituents on D are ashereinabove defined. For example the compound of the formula (XXVI) maybe reduced to a compound of the formula (XXIV), wherein L¹ is hydroxy. Acompound of the formula (XXIV) wherein L¹ is hydroxy, may then beconverted to a compound of the formula (XXIV) wherein L¹ is bromo by,for example, by brominating with phosphorous tribromide.

Alternatively, when p is 0, and in particular when A is a heteroarylgroup, compounds of the formula (XX) may be formed by reacting acompound of the formula (XXVII) with a compound of the formula (XXVIII)in the presence of acetic anhydride or a Lewis acid such as titaniumtetrachloride or zinc chloride. The reaction is conveniently performedin an inert solvent such as dichloromethane in a temperature range ofambient to 100° C.

Compounds of the formula (XX) may also be prepared by dehydrating acompound of the formula (XXIX) using standard methods known in the artfor dehydration. For example with sulphuric or phosphoric acid at anelevated temperature or aluminium oxide at an elevated temperature.

Compounds of the formula (XXIX) may be prepared by reacting a compoundof the formula (XXX) and a compound of the formula (XXVIII) in aGrignard reaction. The compound of the formula (XXX) may be formed byreacting a compound of the formula (XXXI) with magnesium, in an etherialsolvent such as diethyl ether optionally with warming to initiate thereaction. The compound of the formula (XXX) may be reacted, in situ,with the compound of the formula (XXVIII) in a temperature range of -78°C. to reflux.

Alternatively compounds of the formula (XXIX) may be prepared bydeprotonating a compound of the formula (XXVII) with a base and reactingwith a compound of the formula (XXVIII). When A is notelectron-withdrawing, for example when A is phenyl, a strong base may benecessary, for example tert-butyl lithium. The reaction is convenientlycarried out in an etherial solvent such as tetrahydrofuran or diethylether or, depending on the nature of the base, hexane, in a temperaturerange of -78° C. to ambient.

The ether forming reaction between compounds of the formulae (IX) and(X) is typically performed in an inert solvent such as acetone or DMF,in a temperature range of ambient to 60° C., in the presence of a mildbase. Suitable values for L include tosylate, mesylate, triflate andhalo, for example chloro or bromo. When L is bromo, compounds of theformulae (IX) and (X) may, for example, be reacted together in DMF, atambient temperature in the presence of a base such as potassiumcarbonate. When L is hydroxy, the Mitsunobu reaction may be used (O.Synthesis, 1981, 1). For example reacting in tetrahydrofuran or toluenein the presence of diethyl azodicarboxylate and triphenylphosphine.

The compounds of the formula (IX) and (X) may alternatively be reactedtogether using a phase transfer system.

Compounds of the formula (IX) may be prepared as indicated in Schemes IIand III. For example, by removing P from a compound of the formula(IXa). Compounds of the formula (IXa), when n is 2 or 3, may be preparedby reducing a compound of the formula (XX) using standard methods suchas those described for the reduction of compounds of the formula (VIII).

As an alternative example compounds of the formula (IXa) may be preparedby reducing a compound of the formula (XXXII) using standard methodsknown for the reduction of alkynes to alkanes, such as catalytichydrogenation using palladium-on-carbon or Wilkinson's catalyst as thecatalyst.

Compounds of the formula (XXXII) may be prepared by reacting a compoundof the formula (XXXIII) with a compound of the formula (XXXIV), forexample in a trialkylamine solvent such as triethylamine or indimethylformamide (DMF) or in a DMF/trialkylamine mixture, in thepresence of a catalyst such as palladium and preferably also in thepresence of copper (I) idodide, in a temperature range of ambient to100° C.

Compounds of the formula (IX), wherein n is 3, may be prepared bydeprotecting a compound of the formula (IXa) wherein n is 3.

Compounds of the formula (IXa), wherein n is 3, may be prepared byreducing a compound of the formula (XXXV) as shown in scheme III.Suitable conditions are as described for the reduction of compounds ofthe formula (XXXII).

Compounds of the formula (XXXV) are conveniently prepared bydeprotonating a compound of the formula (XXXVII) with a base, such asbutyl lithium, and reacting with a compound of the formula (XXXVI). Inparticular L¹¹ is bromo, chloro, tosylate or mesylate. Most commonly L¹¹is bromo. The reaction is usually carried out in an etherial solventsuch as ether or THF in a temperature range of -78° C. to ambienttemperature.

Compounds of the formula (IX), wherein n is 1, may be prepared byreacting together compounds of the formulae (XXXVIII) and (XXXIX). Thecompounds of the formulae (XXXVIII) and (XXXIX) are reacted together inthe presence of PhB(OH)₂ and trichloroacetic acid (CCl₃ CO₂ H) (orpropanoic acid), in an inert hydrocarbon solvent such as toluene, in atemperature range of 60° C. to reflux. The boronic acid complexintermediate thus formed may be isolated and used in the subsequent stepwithout further purification. This intermediate is converted to acompound of the formula (IX) by reacting with aluminium trichloride(AlCl₃) and borane-tert-butylamine complex (tert-butyl NH₂.BH₃) in aninert solvent, for example a chlorinated hydrocarbon such asdichloromethane, in a temperature range of 0° C. to reflux. C. K. Lau,H. W. R. Williams, S. Tardiff, C. Dufresne, J. Scheigtz, P. C. Belanger,Can. J. Chem., 67, 1384 (1989)).

Alternatively, compounds of the formula (IX), wherein n is 1, may beprepared by reducing a compound of the formula (XXXX). Reactionconditions for the reduction of a carbonyl group to methylene are knownin the art, for example the Clemmensen and Wolff-Kischner reactions.

Compounds of the formula (XXXX) are conveniently prepared by therearrangement of a compound of the formula (XXXXI). The rearrangement iscarried out in the presence of aluminium trichloride at elevatedtemperature, for example 50-150° C., preferably in the absence ofsolvent.

The compounds of the formula (XXXXI) may be prepared by reacting acompound of the formula (XXXVIII) with a compound of the formula(XXXXII) in the presence of a base such as triethylamine and optionallyalso in the presence of dimethylaminopyridine (DMAP). Conveniently thereaction is carried out in an etherial solvent such as diethyl ether, ina temperature range of 0° C. to 100° C., preferably at ambienttemperature.

The reaction between compounds of the formulae (XI) and (XII) is mostsuitable when A is an `activated` heterocycle for example when A ispyridine, pyrimidine, pyrazine or pyridazine and in compounds of theformula (XI) the chloro group is in the 2- or 4-position of thepyridine, 2- or 4-position of the pyrimidine, 2-position of the pyrazineand 3-position of the pyridazine ring. Such ring systems beingoptionally further substituted.

Typically compounds of the formulae (XI) and (XII) are reacted togetherin the presence of a base, such as sodium hydride, potassiumtert-butoxide and lithium hexamethyldisilylamide. The reaction may, forexample be carried out in an etherial solvent such as diethyl ether ortetrahydrofuran in a temperature range of 0° to 60° C.

Compounds of the formula (XI) may be prepared from compounds of theformula (IX), which in one tautomeric form may contain an oxo group.This oxo group may be converted to a chloro group by reacting thecompound of the formula (IX) with a chlorinating agent such as sulphonylchloride, phosphorous trichloride, phosphorous pentachloride or P(O)Cl₃.The reaction is often carried out in the absence of a solvent, althoughN,N-dimethylaniline may be used if acid-sensitive groups are present.Alternatively an inert organic solvent may be used.

The compounds of the formula (X), (XII), (XXI), (XXIV), (XXVII),(XXVIII), (XXXI), (XXXIII), (XXXIV), (XXXVI) and (XXXVIII) are generallyknown in the art or can be made by methods analogous to or similar tothose used in the examples or those known in the art for relatedcompounds.

It is also possible to synthesise certain intermediates and evenprotected compounds using primarily ring synthesis. Here, reference ismade to the compendiums `The Chemistry of Heterocyclic Compounds` E. C.Taylor and A. Weissberger (published by John Wiley and Sons) and`Comprehensive Heterocyclic Chemistry`, A. R Katritzky and C. W Rees(published by Pergamon Press (Elsevier)).

Optional substituents may be converted into other optional substituents.For example an alkylthio group may be oxidised to an alkylsulphinyl oralkysulphonyl group, a nitro group reduced to an amino group, a hydroxygroup alkylated to a methoxy group, or a bromo group converted to analkylthio group.

Various substituents may be introduced into compounds of the formulae(I) and (III) and intermediates in the preparation of compounds of theformulae (I) and (III), when appropriate, using standard methods knownin the art. For example, an acyl group or alkyl group may be introducedinto an activated benzene ring using Friedel-Crafts reactions, a formylgroup by formylation with titanium tetrachloride and dichloromethylethyl ether, a nitro group by nitration with concentrated nitric acidconcentrated sulphuric acid and bromination with bromine ortetra(n-butyl)ammonium tribromide.

It will be appreciated that, in certain steps in the reaction sequenceto compounds of the formula (I), it will be necessary to protect certainfunctional groups in intermediates in order to prevent side reactions.Deprotection may be carried out at a convenient stage in the reactionsequence once protection is no longer required.

As stated hereinbefore compounds of the formula (I) are antagonists ofthe pain enhancing effects of E-type prostaglandins and of value in therelief of mild to moderate pain which, for example, accompaniesinflammatory conditions such as rheumatoid arthritis and osteoarthritis.Certain properties of the compounds may be demonstrated using the testprocedures set out below:

(a) an in-vitro guinea pig ileum assay which assesses the inhibitoryproperties of a test compound against PGE₂ -induced contractions of theileum; ileum was immersed in oxygenated Krebs solution containingindomethacin (4 μg/ml) and atropine (1 μM) and which was maintained at37° C.; the ileum was subject to a tension of 1 g; a control doseresponse curve for PGE₂ -induced contraction of the ileum was obtained;test compound (dissolved in dimethylsulphoxide) was added to the Krebssolution and a dose response curve for the PGE₂ -induced contraction ofthe ileum in the presence of the test compound was obtained; the pA₂value for the test compound was calculated;

(b) an in-vivo assay in mice which assesses the inhibitory properties ofa test compound against abdominal constriction response induced by theintraperitoneal administration of a noxious agent such as dilute aceticacid or phenylbenzoguinone (hereinafter PBQ) using the proceduredisclosed in European Patent Application No. 0218077.

Although the pharmacological properties of the compounds of the formulaI vary with structural change as expected, in general activity possessedby compounds of the formula I may be demonstrated at the followingconcentrations or doses in one or more of the above-mentioned Tests (a)and (b):

Test (a): pA₂ >5.3;

Test (b): ED₃₀ in the range, for example, 0.01-100 mg/kg orally.

No overt toxicity or other untoward effects were noted in Test (b) whencompounds of the formula I are administered at several multiples oftheir minimum inhibitory dose.

Prostaglandin receptors and in particular receptors for PGE₂ have beententatively characterised by Kennedy et al. (Advances in Prostaglandin,Thromboxane and Leukotriene Research, 1983, 11, 327). The known PGE₂antagonist SC-19220 blocks the effect of PGE₂ on some tissues such asguinea pig ileum or dog fundus but not on other tissues such as the cattrachea or chick ileum. Those tissues which did possess SC-19220sensitive mediated effects were said to possess EP₁ receptors. Based onthis compounds of the present invention, possessing activity in Test(a), are EP₁ antagonists.

According to a further feature of the invention there is provided apharmaceutical composition which comprises a compound of the formula (I)or an in-vivo hydrolysable ester thereof or an amide thereof, or apharmaceutically-acceptable salt thereof, in association with apharmaceutically-acceptable diluent or carrier.

The composition may be in a form suitable for oral use, for example atablet, capsule, aqueous or oily solution, suspension or emulsion; fortopical use, for example a cream, ointment, gel, spray or aqueous oroily solution or suspension; for nasal use, for example a snuff, nasalspray or nasal drops; for vaginal or rectal use, for example asuppository or rectal spray; for administration by inhalation, forexample as a finely divided powder or a liquid aerosol; for sub-lingualor buccal use, for example a tablet or capsule; or for parenteral use(including intravenous, subcutaneous, intramuscular, intravascular orinfusion), for example a sterile aqueous or oily solution or suspension.In general the above compositions may be prepared in a conventionalmanner using conventional excipients.

The amount of active ingredient (that is a compound of the formula (I)or a pharmaceutically-acceptable salt thereof) that is combined with oneor more excipients to produce a single dosage form will necessarily varydepending upon the host treated and the particular route ofadministration. For example, a formulation intended for oraladministration to humans will generally contain, for example, from 0.5mg to 2 g of active agent compounded with an appropriate and convenientamount of excipients which may vary from about 5 to about 98 percent byweight of the total composition.

According to a further feature of the invention there is provided acompound of the formula (1) or an in-vivo hydrolysable ester or amide ora pharmaceutically-acceptable salt thereof, for use in a method oftreatment of the animal (including human) body by therapy.

According to a further feature of the invention there is provided theuse of a compound of the formula I, or an in-vivo hydrolysable ester oramide or a pharmaceutically-acceptable salt thereof, in the manufactureof a medicament for use in the relief of pain in the animal (includinghuman) body.

According to a further feature of the invention there is provided amethod for the relief of pain in the animal (including human) body inneed of such treatment which comprises administering to said body aneffective amount of a compound of the formula I, or an in-vivohydrolysable ester or amide or a pharmaceutically-acceptable saltthereof.

As mentioned above, a compound of the formula (I) is useful in treatingthe pain which, for example, accompanies inflammatory conditions such asrheumatoid arthritis and osteoarthritis. In using a compound of theformula I for therapeutic or prophylactic purposes it will generally beadministered so that a daily dose in the range, for example, 0.1 mg to75 mg per kg body weight is received, given if required in divideddoses. In general lower doses will be administered when a parenteralroute is employed. Thus, for example, for intravenous administration, adose in the range, for example, 0.05 mg to 30 mg per kg body weight willgenerally be used. Similarly, for administration by inhalation, a dosein the range, for example, 0.05 mg to 25 mg per kg body weight will beused.

Although the compounds of the formula (I) are primarily of value astherapeutic agents for use in warm-blooded animals (including man), theyare also useful whenever it is required to antagonise the effects ofPGE₂ at the EP₁ receptor, based on test a). Thus, they are useful aspharmacological standards for use in the development of new biologicaltests and in the search for new pharmacological agents.

By virtue of their ability to relieve pain, the compounds of the formulaI are of value in the treatment of certain inflammatory andnon-inflammatory conditions which are currently treated with acyclooxygenase-inhibitory non-steroidal anti-inflammatory drug (NSAID)such as indomethacin, ketorolac, acetylsalicyclic acid, ibuprofen,sulindac, tolmetin and piroxicam or other analgesics such asparacetamol, tramadol, Codein or in some circumstances morphine.Co-administration of a compound of the formula I with a NSAID can resultin a reduction of the quantity of the latter agent needed to produce atherapeutic effect. Thereby the likelihood of adverse side-effects fromthe NSAID such as gastrointestinal effects are reduced. Thus accordingto a further feature of the invention there is provided a pharmaceuticalcomposition which comprises a compound of the formula (I), or an in-vivohydrolysable ester or amide or pharmaceutically-acceptable salt thereof,in conjunction or admixture with a cyclooxygenase inhibitorynon-steroidal anti-inflammatory agent, and a pharmaceutically-acceptablediluent or carrier.

The compounds of the invention may also be used with otheranti-inflammatory agents such as an inhibitor of the enzyme5-lipoxygenase (such as those disclosed in European Patent ApplicationsNos. 0351194, 0375368, 0375404, 0375452, 037547, 0381375, 0385662,0385663, 0385679, 0385680).

The compounds of the formula (I) may also be used in the treatment ofconditions such as rheumatoid arthritis in combination withantiarthritic agents such as gold, methotrexate, steroids andpenicillinamine, and in conditions such as osteoarthritis in combinationwith steroids.

The compounds of the present invention may also be administered indegradative diseases, for example osteoarthritis, withchondroprotective, anti-degradative and/or reparative agents such asDiacerhein, hyaluronic acid formulations such as Hyalan, Rumalon,Arteparon and glucosamine salts such as Antril.

The compositions of the invention may in addition contain one or moreother therapeutic or prophylactic agents known to be of value for thetreatment of pain. Thus for example, a known opiate pain-killer (such asdextropropoxyphene, dehydrocodeine or codeine) or an antagonist of otherpain or inflammation mediators, such as bradykinin, neurokinin andcalcitonin gene related peptides (CGRP), or an alpha₂ -adrenoceptoragonist, a GABA_(B) receptor agonist, a calcium channel blocker, asodium channel blocker, a CCK_(B) receptor antagonist, or an antagonistor modulator of the action of glutamate at the NMDA receptor mayusefully also be present in a pharmaceutical composition of theinvention.

The compounds of the present invention may also be administered in bonediseases such as osteoporosis alone or in combination with calcitoninand bisphosphonates and estrogens.

The invention will now be illustrated in the following non-limitingExamples in which, unless otherwise stated:

(i) evaporations were carried out by rotary evaporations in vacuo andwork-up procedures were carried out after removal of residual solids byfiltration;

(ii) yields are given for illustration only and are not necessarily themaximum attainable;

(iii) the end-products of the formula I have satisfactory microanalysisand their structures were generally confirmed by NMR and mass spectraltechniques;

(iv) intermediates were not generally fully characterised and purity wasassessed by thin layer chromatographic, infra-red (IR) or NMR analysis;

(v) melting points are uncorrected and were determined using a MettlerSP62 automatic melting point apparatus or an oil-bath apparatus; meltingpoints for the end-products of the formula I were determined afterrecrystallisation from a conventional organic solvent such as ethanol,methanol, acetone, ether or hexane, alone or in admixture;

(vi) the following abbreviations have been used:

    ______________________________________                                        DMF             N,N-dimethylformamide;                                          THF tetrahydrofuran;                                                          DMSO dimethylsulphoxide;                                                      AIBN 2,2'-azobisisobutyronitrile                                            ______________________________________                                    

EXAMPLE 1 4-[2-(2-Phenethyl)phenoxymethyl]benzoic Acid

A suspension of methyl 4-[2-(2-phenethyl)phenoxymethyl]-benzoate (2.89g) in ethanol (16 ml) containing aqueous 1N sodium hydroxide solution(16 ml) was stirred at ambient temperature for 16 hours. An additionalportion of ethanol was added (10 ml) and stirring was continued for 16hours. The reaction mixture was concentrated and the solid obtained onaddition of ice-water was removed and discarded. The pH of the aqueousfiltrate was adjusted to 3 by the addition of aqueous 1N hydrochloricacid. The solid which precipitated was filtered, washed with water (10ml) and air dried. Crystallisation of this solid from aqueous ethanolgave 4-[2-(2-phenethyl)-phenoxymethyl]benzoic acid, m.p. 122-123° C.,(2.45 g; 88%).

EXAMPLE 2

The compounds in Table I were prepared from the appropriate methylesters using a similar method to that of example 1.

                                      TABLE I                                     __________________________________________________________________________    1  STR14##                                                                       -                                                                          Compound                                                                        No. R m.p. (°C.) MS Footnote                                         __________________________________________________________________________    1     6-iPr     110.2-110.8                                                                         CI+: 258 (M + NH4).sup.+                                                                  m                                             2 6-NH.sub.2 156.4-157.9 CI+: 348 (M + H)+ m                                  3 6-OH  99.3-100.5 -ve FAB: 347 (M - H).sup.- m                               4 6-Br 138.2-139.2 +veFAB: 411 (M + H).sup.+ g                                5 6-Ph 141.8-142.0 CI+: 426 (M + NH4).sup.+ g                                 6 6-CN 123.7-125.1 CI+: 357 (M').sup.+ c p                                    7 6-hexyl 67.2-68.6 EI+: 416 (M').sup.+ a                                     8 6-C(═N--OH)H  CI+: 376 (MH).sup.+ c                                     9 6-SMe 119.8-120.9 EI+: 378 (M').sup.+ c p                                   10 6-SO.sub.2 Me 140.9-143.6 +veFAB: 433 (M + Na).sup.+ c                     11 6-SOMe 52.9-54.1 CI+: 395 (MH).sup.+ c                                     12 6-CON(Et).sub.2  CI+: 432 (MH).sup.+ a c                                   13 6-NHSO.sub.2 Ph 152.2-152.7 -veFAB: 486 (M - H).sup.- c p                  14 6-N(Et).sub.2 90.8-91.7 +veFAB: 404 (MH).sup.+ c                           15 6-COCH.sub.3 99.1-99.9 +veFAB: 375 (MH).sup.+ c                            16 6-C(═N--OH)CH.sub.3 61.6-68.7 -veFAB: 388 (M - H).sup.-                17 6-Br 4-CN  CI+: 436 (M + H).sup.+ c                                        18 6-CN, 4-Br  EI+: 435 (M+) i                                                19 6-t-Bu, 4-Me 161-162  k p                                                  20 6-Br, 4-OCH.sub.3 117-119  b f                                             21 6-CN, 4-OMe 136-138  n                                                     22 6-OMe, 4-Me 112-114  g                                                     23 4,6,di-t-Bu 173.8-175.1  c                                                 24 4-F, 6-Br 138.4-140    c                                                   25 4-Cl, 6-Me 119.9-126.1  c                                                  26 4,6-di-Br 150.4-151.5  c                                                   27 4-Me, 6-CN 120.5-121.9  c                                                  28 4-Br 167-168 -veFAB: 409, 411 (M - H) o p                                  29 4-NO.sub.2 198-199 CI+: 395 (M + NH4) n                                    30 4-CH.sub.3, 6-Br 122-123 -veFAB: 423 (M - H).sup.- b p                     31 4,6di-F  98-100 +veFAB: 368 (M°).sup.+                              32 4-OCH.sub.3 138-140 +veFAB: 363 (M + H).sup.+ c p                          33 4-CH.sub.3 154-155 +veFAB: 347 (M + H).sup.+ g p                           34 4-hexyl 95-97 +veFAB: 417 (M + H).sup.+ p q                                35 4-OH 175-177 EI+: 348 (M).sup.+ n p s                                      36 4-C(═NOH)CH.sub.3 198-200 +veFAB: 390 (M + H).sup.+ c                  37 4-CH.sub.2 CN 152-156 +veFAB: 372 (M + H).sup.+ k                          38 Not used                                                                   39 4-COCH.sub.3 165-167 -veFAB: 373 (M - H).sup.- h                           40 4-Cl 166-167 +veFAB: 366 (M.).sup.+ d                                      41 4-CH.sub.2 OH 168-170 +veFAB: 262 (M.).sup.+ c                             42 4-CON(Et).sub.2  +veFAB: 432 (M + H).sup.+ j                               43 4-CO.sub.2 H  -veFAB: 375 (M - H).sup.- m                                  44 5-Br 161-162 +veFAB: 411 (M + H).sup.+ e p                                 45 5-OH 171-172 CI+: 349 (M + H).sup.+ k p q u                                46 4-C(═N--OH)H  -veFAB: 374 (M - H).sup.- c                              47 4-SMe 136-138 +veFAB: 379 (M + H).sup.+ g                                  48 4-SOMe 178-181 +veFAB: 395 (M + H).sup.+ c r                               49 4-SO.sub.2 Me  -veFAB: 409 (M - H).sup.- k q                               50 5-CN 192-194 EI+: 357 (M').sup.+ i p                                       51 5-Cl 160-161 EI.sup.+ : 384 (M + NH.sub.4).sup.+ e q p                     52 5-OCH.sub.3 170-171 CI+: 363 (M + H).sup.+ c p                             53 5-Me 138-139 EI.sup.+ : 346 (M°).sup.+ c p                          54 4-CN 190-191 -veFAB: 356 (M - H).sup.- o p                                 55 6-OCH.sub.3   110-111.9 CI.sup.+ : 380 (M + NH.sub.4).sup.+ c                                               56 6-Cl 124-125 -veFAB: 365 (M -                                             H).sup.- c p                                  57 6-Me   106-106.5 -veFAB: 345 (M - H).sup.- c p                             58 6-NO.sub.2 142-143 -veFAB: 376 (M - H).sup.- c p                           59 4-CH.sub.2 SO.sub.2 Ph 193-195 -veFAB: 485 (M - H).sup.- g t             __________________________________________________________________________     4-[6-Bromo-2-(2-phenethenyl)phenoxymethyl]benzoic acid was also prepared      using a similar method to that of example 1, using 2 equivalents of base      and precipitating with acetic acid.                                           MS (CI.sup.+): 408/410 [M].sup.+.                                             Footnotes                                                                     a) Purified by chromatography using methanol/dichloromethane as eluant.       b) Purified by chromatography using diethyl ether/hexane as eluant.           c) 2.0 equivalents of base used.                                              d) 2.4 equivalents of base used.                                              e) 2.5 equivalents of base used.                                              f) 2.65 equivalents of base used.                                             g) 3.0 equivalents of base used.                                              h) 3.3 equivalents of base used.                                              i) 3.6 equivalents of base used.                                              j) 3.7 equivalents of base used.                                              k) 4.0 equivalents of base used.                                              l) 4.35 equivalents of base used.                                             m) 5.0 equivalents of base used.                                              n) 7.0 equivalents of base used.                                              o) 8.0 equivalents of base used.                                              p) Crystallised from ethanol/water.                                           q) Extracted with ethyl acetate.                                              r) Triturated with diethyl ether.                                             s) Hydroxy group was protected by pivaloyl which fell off in the ester        hydrolysis.                                                                   t) Precipitated with acetic acid.                                             u) Methyl ester compound with 5hydroxy group protected by a pivaloyl grou     was subjected to hydrolysis in ethanol to give the 5hydroxy ethyl ester       which was subjected to repeated hydrolysis to give the acid.             

EXAMPLE 34-[2-(2-Phenethyl)-6-(methylsulphinylmethyl)phenoxvmethyl]benzoic Acid

t-Butyl 4-[2-(2-phenethyl)-6-(methylsulphonyl)phenoxymethyl]-benzoate(0.441 g, 0.95 mMole) was treated with formic acid (3 ml) and thereaction mixture stirred at ambient temperature for 3 hours. The mixturewas then diluted with water and the product which precipitated wasfiltered, washed with water and dried to give4-[2-(2-phenethyl)-6-(methylsulphinylmethyl)phenoxymethyl]benzoic acid.MS FAB⁻ : 407 [M-H]⁻ m.p. 122.5-124.6° C.

EXAMPLE 4

The compounds in Table II were prepared from the appropriate t-butylester using a similar method to that of example 3, with variation inconditions noted.

                  TABLE II                                                        ______________________________________                                        1  STR15##                                                                      Com-                                                                          pound    Foot-                                                                No. R m.p. (° C.) and MS Conditions notes                            ______________________________________                                        1     6-CHO      m.p.         0° C.; 0.25 hours                            140.4-141.8° C. dilute with water                                      MS (CI.sup.+): 360 (M°).sup.+  and filter                               precipitate.                                                               2 6-CO.sub.2 CH.sub.3 m.p. 0° C.; 1.5 hours;                             132-4-133.0° C. 0.4 g of ester                                         MS (-ve FAB): 4 ml of acid;                                                   389(MH).sup.- precipitate filtered                                          3 6-CH.sub.2 CN m.p. Ambient a                                                  120.5-121.6° C. temperature;                                           MS (+ve FAB): 1.5 hours; 0.2 g                                                372 (M + H).sup.+ of ester; 2 ml of                                            acid; dilute with                                                             water and filter                                                              precipitate.                                                               4 6-CH.sub.2 SO.sub.2 Ph m.p. Ambient b                                         140.2-142.2° C. temperature;                                           MS (CI.sup.+): 504 1.5 hours; 0.84 g                                          (M + NH.sub.4).sup.+ of ester; 3 ml of                                         acid; 18 hours;                                                               dilute with water                                                             and filter                                                                    precipitate                                                                5 6-CH.sub.2 OCH.sub.3 m.p. Ambient a                                           134.7-136.0° C. temperature;                                           MS (CI): 3 hours; 0.35 g of                                                   394 (M + NH.sub.4).sup.+                                                      ester; 3 ml of acid;                                                          filter precipitate                                                          6 6-CH.sub.2 SO.sub.2 CH.sub.3 m.p. Ambient                                     138.1-140.3° C. temperature;                                           MS (-ve FAB): 423 16 hours; 0.2                                               (M - H) mmol of ester;                                                         2 ml of acid;                                                                 filter precipitate                                                         7 6-CONHMe m.p. Ambient                                                         147.3-148.9° C. temperature;                                           MS (-ve FAB): 388 18 hours: 0.62                                              (M - H).sup.- mmol of ester;                                                   2 ml of acid;                                                                 dilute with water                                                             and filter                                                                    precipitate                                                                8 4-CO.sub.2 Me m.p. 177-179° C. 30° C.; 4 hours;                                                        MS (+veFAB): 391 1 ml of acid;         (M + H).sup.+ dilute with ether,                                               filter precipitate                                                            and wash with                                                                 diethyl ether.                                                           ______________________________________                                         Footnotes                                                                     a Crystallised from ethanol/water                                             b Triturated with ethyl ether                                            

EXAMPLE 55-[4-(4-bromo-2-(2-phenethyl)phenoxymethyl)phenyl]-1H-tetrazole

Sodium azide (1.33 g) was added to a mixture of4-[4-bromo-2-(2-phenethyl)phenoxymethyl]benzonitrile (2.05 g) andammonium chloride (1.09 g) in DMF (25 ml) and the mixture was stirredand heated at 125° C. for 40 hours. The cooled reaction mixture waspoured into ice-water (100 ml) and the pH of the mixture adjusted to 4-5with aqueous 2N hydrochloric acid. The solid obtained on filtration waswashed with water (50 ml) and air dried. The solid was purified bysubjecting to chromatography on silica, eluting with a mixture ofmethanol and dichloromethane (1:9 v/v) to give5-[4-(4-bromo-2-(2-phenethyl)phenoxymethyl)phenyl]-1H-tetrazole 1.8 g(78%) m.p. 183-5° C.

EXAMPLE 6

The compounds of Table III were prepared using a similar method to thatof example

                                      TABLE III                                   __________________________________________________________________________    2  STR16##                                                                       -                                                                          Compound Equivalents of NH.sub.4 Cl                                                                  Time                                                                              m.p. (0° C.)                                  No. R and NaN.sub.3 to nitrile T ° C. (hours) and MS Footnotes       __________________________________________________________________________    1    4-hexyl                                                                           4         130 5   mp 135-137                                                                            a                                                 (+ve FAB):                                                                    441 (M + H).sup.+                                                        2 4-OH 5 130 5 (-ve FAB): b                                                        371 (M - H).sup.-                                                        3 4-Cl 4 125 40  mp 170-173 c                                                      (+ve FAB):                                                                    (M + Na).sup.+                                                           4 4-OCH.sub.3   3.8 125 48  mp 126-127 d                                           (+ve FAB):                                                                    387 (M + H).sup.+                                                        5 6-iPr 4 125 5 mp 129.4-130.2 e                                              6 6-Ph 4 120 5 mp 146.5-147.8 e                                               7 6-Br 4 125 5 mp 113-114.5 e                                                 8 6-hexyl 4 130 5 (+ve FAB): f                                                     441 (M + H).sup.+                                                        9 H -- 125 48  mp 146-8 h                                                     10  5-Cl -- 150 3 (+ve FAB): 391 c, g                                              (M + H).sup.+                                                            11  5-MeO -- 125 48  mp 165-7 b                                             __________________________________________________________________________     Footnotes                                                                     a Purified by chromatography eluting with methanol/dichloromethane and        triturating the product with hexane.                                          b Purified by chromatography eluting with methanol/chloroform and             triturating with ethyl ether.                                                 c Purified by chromatography eluting with methanol/dichloromethane.           d Purified by extracting with ethyl acetate and subjecting to                 chromatography eluting with methanol/dichoromethane, then triturating the     product with ethyl ether.                                                     e Purified by crystallising from ethanol/water.                               f Purified by extracting with ethyl acetate and subjecting to                 chromatography eluting with methanol/dichloromethane.                         g NMethyl-2-pyrrolidine was used as the solvent.                              h Purified by chromatography, eluting with methanol/dichloromethane and       recrystallising from ethyl acetate/hexane.                               

EXAMPLE 7N-(2-Hydroxyethyl)-4-[2-(2-phenethyl)phenoxymethyl]benzenecarboxamide

A mixture of methyl 4-[2-(2-phenethyl)phenoxymethyl]benzoate (0.5 g) in2-aminoethanol (6 ml) was heated at 160° C. under argon for 3 hours.Water (10 ml) was added to the cooled reaction mixture which wasextracted three times with ethyl acetate (25 ml each time). The combinedethyl acetate extracts were dried (MgSO₄). The residue obtained onremoval of the solvent was purified by chromatography on silica, elutingwith a mixture of ethyl acetate and dichloromethane (1:1 v/v), andcrystallised from a mixture of ethyl acetate and hexane to giveN-(2-hydroxyethyl)-4-[2-(2-phenethyl)phenoxymethyl]benzenecarboxamide,(0.23 g; 44%) m.p. 95-7° C.

EXAMPLE 8

The compounds of Table IV were prepared using a similar method to thatdescribed in Example 7, except using the appropriate ester in place ofmethyl 4-[2-(2-phenethyl)phenoxymethyl]benzoate.

                  TABLE IV                                                        ______________________________________                                        1  STR17##                                                                      Compound                                                                      No. R m.p. °C.                                                       ______________________________________                                        1               5-MeO   waxy solid                                              2 5-Me 115-7                                                                  3 5-Cl   115-116.5                                                            4 6-MeO 54-55                                                                 5 6-Me 79.5-81                                                              ______________________________________                                    

EXAMPLE 9N-(3-Pyridylmethyl)-4-[2-(2-phenethyl)phenoxymethyl]benzenecarboxamide

a) A solution of 4-[2-(2-phenethyl)phenoxymethyl]-benzenecarbonylchloride (0.4 g) in dichloromethane (2.5 ml) was added to a mixture oftriethylamine (0.48 ml) and 3-aminomethylpyridine (0.13 ml) indichloromethane (5 ml) at 0° C. The reaction mixture was allowed to warmto ambient temperature and was stirred for 16 hours. The reactionmixture was diluted with ethyl acetate (20 ml) and the solution washedconsecutively with water (15 ml), saturated aqueous sodium bicarbonatesolution (15 ml) and brine (15 ml). The ethyl acetate solution was dried(MgSO₄) and the solid obtained on removal of the solvent was purified bysubjecting to chromatography on silica, eluting with ethyl acetate, togiveN-(3-pyridylmethyl)-4-[2-(2-phenethyl)phenoxymethyl]-benzenecarboxamide(0.23 g; 48%) m.p. 142-4° C.

b) The 4-[2-(2-phenethyl)phenoxymethyl]benzenecarbonyl chloride used asstarting material was prepared as follows:

Oxalyl chloride (0.24 ml) was added to a solution of4-[2-(2-phenethyl)phenoxymethyl]benzoic acid (0.76 g) in dichloromethane(15 ml) containing one drop of DMF maintained at 0° C. The reactionmixture was allowed to warm to ambient temperature and was stirred atthis temperature for 3 hours. The reaction mixture was evaporated todryness to give 4-[2-(2-phenethyl)phenoxymethyl]-benzenecarbonylchloride as a gum which was used without further purification.

EXAMPLE 10

The compounds of Table V were prepared using a similar method to thatdescribed in Example 9, except using the appropriate amine in place of3-aminomethylpyridine.

                                      TABLE V                                     __________________________________________________________________________    1  STR18##                                                                       -                                                                          Compound                              M.p. (° C.)                        No. R.sup.1 R B and MS Footnotes                                            __________________________________________________________________________       1 H                                                                                                                             2  STR19##                                                                    3  149-150 g                                                                    -  2 5-MeO                                                                  4  " 154-5 g                                                                    -  3 5-MeO                                                                  2  " 101-2 c                                                                    -  4 5-Me " "                                                               114-6 g                     -  5 5-Me                                                                                                                       4  " 159-160 g                                                                  -  6 5-Cl                                                                   2  " 128-9 c                                                                    -  7 5-Cl                                                                   4  " 153-4 g                                                                    -  8 5-MeO                                                                  --CH.sub.2 CH.sub.2                                                           CH.sub.3 " 85-6 i                                                               9 4-CH.sub.3 " "                                                            m.p. 97-99, a                                                                      MS(CI.sup.+):388                                                         (M + H).sup.+                                                                  10 4-CH.sub.3                                                                --CH.sub.2 CH.sub.2                                                           OH " m.p. 112-114 b                                                                MS(CI.sup.+):390                                                         (M + H).sup.+                                                                   - 11 4-CH.sub.3                                                             4  " m.p. 159-161                                                             MS(+veFAB):437(M +                                                            H).sup.+ b                  - 12 4-OCH.sub.3 --CH.sub.2 CH.sub.2 CH.sub.3 " m.p. 99-100 c                    MS(CI.sup.+):404(M + H).sup.+                                             13 4-OCH.sub.3 --CH.sub.2 CH.sub.2 OH " m.p. 107-108 c                            MS(CI.sup.+):406(M + H).sup.+                                              - 14 4-OCH.sub.3                                                                                                                4  " m.p. 136-138                                                             MS(+veFAB):453(M +                                                            H).sup.+ c                  - 15 4-CN --CH.sub.2 CH.sub.2 CH.sub.3 " m.p. 93-95 c                            MS(+veFAB):399(M + H).sup.+                                               16 4-CN --CH.sub.2 CH.sub.2 OH " m.p. 113-115° C. d                        MS FAB.sup.+ :401(M + H).sup.+                                             - 17 4-CN                                                                                                                       4  " m.p. 139-141.deg                                                         ree. C. MS(+veFAB):44                                                         8(M + H).sup.+ e                                                                - 18 4-CN                                                                   2  " m.p. 93-95                                                               MS(+veFAB):399(M +                                                            H).sup.+ e                  - 19 4-Cl --CH.sub.2 CH.sub.2 OH " m.p. 114-116 e                                MS(+veFAB):410(M + H).sup.+                                                - 20 6-Cl                                                                                                                       4  " m.p. 109.6-110.8                                                          e                          - 21 6-NO.sub.2                                                                                                                 2  " m.p. 77.4-78.6                                                           e                           - 22 6-NO.sub.2                                                                                                                 4  " m.p. 103.9-105.2                                                          e                          - 23 6-NO.sub.2 --CH.sub.2 CH.sub.2 CH.sub.3 " m.p. 75.2-76.1 f                                                                  24 6-iPr --CH.sub.2                                                          CH.sub.2 OH " oil                                                             MS(EI.sup.+):417[M.de                                                         gree.].sup.+ f                                                                  - 25 6-iPr                                                                  4  " m.p. 89.5-90.7                                                           f                           - 26 6-CN --CH.sub.2 CH.sub.2 OH " m.p. 92.1-93.5 e, f                        - 27 6-CN                                                                                                                       4  " m.p. 136.5-13.7                                                          e, f                        - 28 6-CN --CH.sub.2 CH.sub.2 CH.sub.3 " m.p. 100.8-101.3 e, f                                                                   29 4-CO.sub.2 Me                                                             --CH.sub.2 CH.sub.2                                                           OH " m.p. 118-120.deg                                                         ree. C. c                      MS(+veFAB.sup.+):434(M + H).sup.+ c                                       30 4-Br " " m.p. 120-121 c                                                        MS(CI.sup.+)456:(M + H).sup.+                                             31 4-Br --CH.sub.2 CH.sub.2 CH.sub.3 " m.p. 118-119 c                             MS(CI.sup.+):452(M + H).sup.+                                              - 32 4-Br                                                                                                                       4  " m.p. 149-151                                                             MS(CI.sup.+):501(M +                                                          H).sup.+ c                  - 33 4-hexyl --CH.sub.2 CH.sub.2 OH " m.p. 94-96 c                               MS(+veFAB):460(M + H).sup.+                                                - 34 4-NO.sub.2                                                                                                                 4  " m.p. 168-169                                                             MS(+veFAB):468(M +                                                            H).sup.+ g, k                                                                   - 35 6-Me                                                                   2  " m.p. 113.4-114.2                                                          f, e                       - 36 6-Me                                                                                                                       4  " m.p. 104.0-104.8                                                          f, e                       - 37 6-Me --CH.sub.2 CH.sub.2 CH.sub.3 " m.p. 67.8-68.6 f, e                 38 6-Me --CH.sub.2 CH.sub.2 CN " m.p. 111.8-112.5 f, e                        39 6-Cl --CH.sub.2 CH.sub.2 OH " m.p. 76.5-78.1 e                              - 40 6-Cl                                                                                                                       2  " m.p. 99.8-100.8                                                          f                           - 41 6-Br --CH.sub.2 CH.sub.2 OH " m.p. 93.5-95.0 b                           - 42 6-Br                                                                                                                       4  " m.p. 105.1-106.0                                                          b                          - 43 6-Br --CH.sub.2 CH.sub.2 CH.sub.3 " m.p. 104.2-105.0                    44 5-Br " " m.p. 131-132 b                                                        MS(EI.sup.+):452(M°).sup.+                                         45 5-Br --CH.sub.2 CH.sub.2 OH " m.p. 123-125 b                                   MS(CI.sup.+):456(M + H)                                                    - 46 5-Br                                                                                                                       4  " m.p. 152-153                                                             MS(+veFAB):501/503                                                            (M + H ).sup.+ b                                                                - 47 5-CN --CH.sub.                                                         2 CH.sub.2 OH " m.p.                                                          142-144 b                      MS(CI.sup.+):401(M - 1H).sup.+                                             - 48 5-CN                                                                                                                       4  " m.p. 167-169                                                             MS(CI.sup.+):448(M +                                                          H).sup.+ c                  - 49 4-Me,6-tBu " " MS(+veFAB):493(M + H).sup.+ c                            50 4-Me,6-tBu --CH.sub.2 CH.sub.2 OH " m.p. 81-83 MS(CI.sup.+):446(M +                                                           H).sup.+ c                 51 4-Me,6-tBu --CH.sub.2 CH.sub.2 CH.sub.3 " m.p. 91-93 MS(CI.sup.+):444                                                         (M + H).sup.+ c                                                                 - 52 H --CH.sub.2                                                           CH.sub.2 OH                                                                   5  m.p. 114-116                                                               MS(+veFAB):377(M +                                                            H).sup.+ h                  - 53 H                                                                                                                          4  " m.p. 164-166                                                             MS(+veFAB):424(M +                                                            H).sup.+ h                  - 54 H --CH.sub.2 CH.sub.2 CH.sub.3 " m.p. 100-102 i                             MS(CI.sup.+):376(M + H).sup.+                                             55 5-OCH.sub.3 " " MS(CI.sup.+):406(M + H).sup.+ i                             - 56 5-OCH.sub.3                                                                                                                4  " m.p. 150-152                                                             MS(CI.sup.+):454(M +                                                          H).sup.+ h                  - 57 5-OCH.sub.3 --CH.sub.2 CH.sub.2 OH " m.p. 104-108 h                         MS(+veFAB):407(M + H).sup.+                                               58 4-CN " " MS(+veFAB):402(M + H).sup.+ h                                      - 59 6-Ph                                                                                                                       6  STR46##                                                                    7  m.p. 232.8-234.1                                                           MS(+veFAB):498(M +                                                            Na).sup.+ f                 - 60 6-CN                                                                                                                       6  STR48##                                                                    7  m.p. 250.0-250.5                                                           MS(+veFAB):425(M +                                                            H).sup.+ f, l            __________________________________________________________________________     Footnotes                                                                     a Purified by chromatography using ethyl acetate/hexane as the eluant and     triturating the product with toluene/hexane.                                  b Purified by chromatography using ethyl acetate/hexane as the eluant and     triturating the product with ethyl ether.                                     c Purified by chromatography using ethyl acetate/hexane as the eluant.        d Purified by chromatography using ethyl acetate/dichloromethane as the       eluant.                                                                       e Purified by triturating with ethyl ether.                                   f Purified by chromatography using methanol/dichloromethane as the eluant     g Purified by chromatography using ethyl acetate as eluant.                   h Purified by chromatography using methanol/ethyl acetate as eluant and       triturating the product with ethyl ether.                                     i Purified by chromatography using ethyl acetate/hexane as eluant and         triturating the product with ethyl ether/hexane.                              j Purified by chromatography using methanol/ethyl acetate as eluant and       triturating the product with diethyl ether/ethyl acetate.                     k Product triturated with acetone.                                            l Product triturated with ethyl ether.                                   

EXAMPLE 11N-(2-Pyridylmethyl)-4-[6-methoxy-2-(phenethyl)phenoxymethyl]benzenecarboxamide

Triethylamine (0.24 ml) was added to a solution of4-(6-methoxy-2-(2-phenethyl)phenoxymethyl)benzoic acid (0.6 g) and2-aminomethylpyridine (0.20 ml) in DMF (20 ml) maintained at 5° C.Diphenylphosphoryl azide (0.37 ml) was added to this mixture and thesolution was allowed to warm to ambient temperature and was stirred atthis temperature for 16 hours. Water (50 ml) was added to the reactionmixture. This mixture was extracted with ethyl acetate (2×50 ml) and theethyl acetate extracts washed with water (50 ml) and dried (MgSO₄). Theresidue obtained on evaporation of the solvent was purified bysubjecting to chromatography on silica eluting with a mixture ofmethanol and dichloromethane (1:49 v/v) to giveN-(2-pyridylmethyl)-4-[6-methoxy-2-(2-phenethyl)phenoxymethyl]benzenecarboxamide(0.5 g; 66%) m.p. 126-7° C.

EXAMPLE 12

The compounds of Table VI were prepared using a similar method to thatoutlined in Example 11, except using the appropriate amine in place of2-aminomethylpyridine.

                                      TABLE VI                                    __________________________________________________________________________    1  STR50##                                                                       -                                                                          Compound                               m.p. (° C.)                       No. R.sup.1 R B and MS Footnotes                                            __________________________________________________________________________       1 5-OH                                                                                                                          2  STR51##                                                                    3  185-7 #                  -  2 6-MeO " " 74                                                             3 5-OH --CH.sub.2 CH.sub.2 OH " waxy solid                                    4 4-OH --CH.sub.2 CH.sub.2 OH " m.p. 116-119 a                                   MS(+veFAB):392(M + H).sup.+                                                5 6-OH --CH.sub.2 CH.sub.2 OH " m.p. 135.1-136.6 b                            -  6 6-OH                                                                                                                       2  " m.p. 123.7-125.8                                                          b                          -  7 6-CH.sub.2 SOCH.sub.3 --CH.sub.2 CH.sub.2 OH " Gum                          MS(CI.sup.+):452(M + H).sup.+                                              8 6-SMe " " Gum                                                                  MS(CI.sup.+):422(M + H).sup.+                                              9 6-CH.sub.2 OCH.sub.3 " " Gum                                                   MS(CI.sup.+):420(M + H).sup.+                                             10 6-CH.sub.2 SO.sub.2 Ph " " m.p. 45.6-55.0                                   - 11 6-CN                                                                                                                       2  STR54##                                                                    4  m.p. 112.8-114                                                             MS(+veFAB.sup.+):449(                                                         M + H).sup.+                                                                    - 12 6-Br --CH.sub.                                                         2 CH.sub.2 OH                                                                 5  Gum MS(+veFAB.sup.                                                         +):455/457(M +                                                                H).sup.+                    - 13 5-OH " " m.p. 146-148                                                       MS(+veFAB.sup.+):393(M + H).sup.+                                          - 14 5-OH                                                                                                                       4  " m.p. 186-188                                                             MS(+veFAB.sup.+):440(                                                         M + H).sup.+                                                                    - 15 6-NH.sub.2                                                             2  STR58##                                                                    3  m.p. 109.7-110.4                                                           MS(CI.sup.+):438(M +                                                          H).sup.+ c                  - 16 6-NH.sub.2                                                                                                                 4  " m.p. 87.7-89.0                                                           MS(CI.sup.+):438(M +                                                          H).sup.+ c                  - 17 6-NH.sub.2 --CH.sub.2 CH.sub.2 CH.sub.3                                                                                    3  Oil MS(CI.sup.+):3                                                         89(M + H).sup.+ c                                                               - 18 6-NH.sub.2                                                             --CH.sub.2 CH.sub.2                                                           OH " Gum c                     MS(CI.sup.+):391(M + H).sup.+                                           __________________________________________________________________________     Footnotes                                                                     a Purified by chromatography using ethyl acetate/hexane/acetic acid as        eluant and triturating the product with ethyl ether.                          b Purified by chromatography using methanol/dichloromethane as eluant and     triturating the product with ethyl ether.                                     c Purified by chromatography using methanol/dichloromethane as eluant.   

EXAMPLE 13 2-[2-(2-Phenethyl)-6-bromophenoxymethyl]-4-thiazolecarboxylicAcid

A solution of ethyl2-[2-(2-phenethyl)-6-bromophenoxymethyl]-4-thiazolecarboxylate (1.33 g,2.98 mmol) in ethanol (10 mL) and THF (10 mL) was treated with 1N NaOH(6 mL). The reaction was stirred at ambient temperature overnight andthen partially evaporated and diluted with water. Acetic acid was addedto precipitate the title product, which was filtered and dried (1.21 g,97%).

NMR: (250 MH₂,DMSO-d₆): δ8.14 (s, 1H), 7.53 (dd, 1H), 7.18 (m, 7H), 5.2(s, 2H), 2.9 (m, 4H).

Preparation of the starting material:

A solution of ethyl 2-methyl-4-thiazolecarboxylate [JCS 1946, 87, E. R.H. Jones, F. A. Robinson, M. N. Strachan] (5.0 g, 29.2 mmol) in CCl₄ (30ml) was treated with N-bromosuccinimide (5.2 g, 29.2 mmol) andbenzoylperoxide (0.03 g). The reaction was heated to reflux whileirradiating with a strong lamp for 21/2 hours. The reaction mixture wasallowed to cool to ambient temperature, filtered and evaporated. Theresidue was purified by chromatography (eluant: CH₂ Cl₂) to obtain ethyl2-bromomethyl-4-thiazolecarboxylate (2.27 g, 31%).

NMR (250 MH, DMSO-d₆): δ8.55 (s, 1H), 5.04 (s, 2H), 4.30 (g, 2H), 1.32(t, 3H).

A solution of 6-bromo-2-(2-phenethyl)phenol (1.2 g, 4.33 mmoles) in DMF(5 mL) was treated with K₂ CO₃ (1-2 g, 8.7 mmoles) and ethyl2-bromomethyl-4-thiazole carboxylate (1.08 g, 4.32 mmoles). The reactionwas stirred at ambient temperature overnight and then partitionedbetween ethyl acetate/H₂ O. The organic phase was washed well withwater, dried over (MgSO₄) and evaporated. The residue was purified bychromatography (eluant: CH₂ Cl₂ /hexane) to give ethyl2-[2-(2-phenethyl)-6-bromophenoxymethyl]-4-thiazolecarboxylate (1.425 g,74%).

NMR (250 MH₂, DMSO-d₆): δ8.60 (s, 1H), 7.54 (dd, 1H), 7.33 (dd, 1H),7.18 (m, 6H), 5.27 (s, 2H), 4.34 (f, 2H), 2.9 (m, 4H), 1.33 (t, 3H).

EXAMPLE 14

The compounds of Table VII were prepared using a similar method to thatof Example 13.

                  TABLE VII                                                       ______________________________________                                        6  STR62##                                                                      Compound                                                                      No. R.sup.1 m.p. (° C.) and MS Footnotes                             ______________________________________                                        1       4-OCH.sub.3                                                                            m.p. 136-137                                                     MS(+veFAB):370(M + H).sup.+                                                 2 4-Br m.p. 171-174 a                                                           MS(+veFAB):418(M + H).sup.+                                                 3 6-CN MS(+veFAB).sup.+ :365(M + H).sup.+ b                                 ______________________________________                                         Footnotes                                                                     a Purified by chromatography using ethyl acetate/acetic acid as eluant.       b Recrystallised from ethanol.                                           

EXAMPLE 15 Preparation ofN-(3-pyridylmethyl)-2-[2-(2-phenethyl)-4-methoxyphenoxymethyl]-4-thiazoleamide

To a cooled solution (5° C.) of triethylamine (0.24 g, 2.4 mmole) and3-aminomethylpyridine (0.097 g, 0.89 mmole) in dichloromethane (6 ml)was added a solution of2-[2-(2-phenethyl)-4-methoxyphenoxymethyl]-4-thiazolylchloride (preparedfrom compound 1 of Table VII, Example 14, using a similar method to thatof the first part of Example 18) (0.8 mmoles) in dichloromethane (5.3ml). The reaction was allowed to warm to ambient temperature and allowedto stand for 60 hours. The reaction mixture was evaporated. The residuewas purified by chromatography (ethyl acetate/hexane) to give the titleproduct (0.205 g, 56%), m.p 113-115° C.

MS (FAB+): 460 (M+H)+.

EXAMPLE 16

The compounds of Table VIII were prepared using a similar method to thatof Example 15.

                                      TABLE VIII                                  __________________________________________________________________________    1  STR63##                                                                       -                                                                          Compound                                                                        No. R.sup.1 R m.p. (° C.) and MS Footnotes                           __________________________________________________________________________      1 not used                                                                    2 4-OCH.sub.3 --CH.sub.2 CH.sub.2 OH m.p. 129-131° C. a                   MS(CI).sup.+ :413(M + H).sup.+                                             3 4-OCH.sub.3 CH.sub.2 CH.sub.2 CH.sub.3 m.p. 68-70° C. a                                                   MS(CI.sup.+):411(M + H).sup.+                                               - 4 4-Br                                                                    2  m.p. 106-108 MS(CI.sup.+):508(M +                                          H).sup.+ a                                    - 5 4-Br --CH.sub.2 CH.sub.2 OH m.p. 145-147 a                                  MS(CI.sup.+):461(M + H).sup.+                                              6 6-Br --CH.sub.2 CH.sub.2 CH.sub.3 m.p. 81.7-83.0 b                             MS(+veFAB):459/461(M + H).sub.+                                            7 6-Br --CH.sub.2 CH.sub.2 OH Gum c                                              MS(CI.sup.+):461/463(M + H).sup.+                                           - 8 6-Br                                                                                                      2  m.p. 110-110.9 MS(CI.sup.+):508/510(                                       M + H).sup.+ c                             __________________________________________________________________________     Footnotes                                                                     a Purified by chromatography using ethyl acetate/hexane as eluant.            b Purified by chromatography by using methanol/dichloromethane as eluant.     c Purified by chromatography using methanol/dichloromethane as eluant and     triturating the product with ethyl ether.                                

EXAMPLE 17

The compounds of Table IX were prepared using a similar method to thatof example 13, from the appropriate 2-(2-phenethyl)phenol and ethyl2-bromomethyl-5-thiazolecarboxylate (Reference Example 18).

                  TABLE IX                                                        ______________________________________                                        3  STR66##                                                                      Compound                                                                      No. R Data Footnotes                                                        ______________________________________                                        1        4-Me    m.p. 157-160      a                                              MS(+veFAB):354(M + H).sup.+                                                 2 6-Br m.p. 143.1-145.0                                                         MS(+veFAB):418/420(M + H).sup.+                                           ______________________________________                                         Footnotes                                                                     a Purified by chromatography using ethyl acetate/hexane as eluant.       

EXAMPLE 18N-(2-Hydroxyethyl)-2-[2-(2-phenethyl)-6-bromophenoxymethyl]-5-thiazoleamide

A solution of 2-[6-bromo-2-(2-phenethyl)phenoxymethyl]-5-thiazolecarboxylic acid (Table IX, Compound 2) (1.029 g, 2.4 mmol) indichloromethane (10 ml) was treated with oxalyl chloride (0.459 g, 3.6mmol) and two drops of DMF. The reaction was stirred at ambienttemperature for 1 hour. The reaction mixture was evaporated to drynessto give the acid chloride which was then taken up in a measured amountof dry dichloromethane (9 ml).

To a cooled (5° C.) stirred solution of ethanolamine (0.061 g, 1 mmol)and triethylamine (0.101 g, 1 mmol) in dichloromethane (4 ml) was addedan aliquot of the acid chloride solution prepared above (0.8 mmol, 3ml). The reaction was allowed to warm to ambient temperature and stirredovernight. The reaction mixture was evaporated to dryness and theresidue purified by chromatography (methanol/CH₂ Cl₂) to give the titleamide (0.26 g, 71%) as an off-white solid. m.p. 102.6-104.8° C. MS(CI⁺):461/463 (M+H)⁺.

EXAMPLE 19

The compounds of Table X were prepared using a similar method that ofexample 18.

                                      TABLE X                                     __________________________________________________________________________    4  STR67##                                                                       -                                                                          Compound                                                                        No. R.sup.1 R m.p. (° C.) and MS Footnotes                           __________________________________________________________________________    1     4-CH.sub.3                                                                        --CH.sub.2 CH.sub.2 CH.sub.3                                                             m.p. 106-107  a                                               MS(+veFAB):395(M + H).sup.+                                                 - 2 4-CH.sub.3                                                                                                2  m.p. 164-165 MS(CI.sup.+):444(M +                                          H).sup.+ b                                    - 3 6-Br " Gum c                                                                MS(+veFAB):508/510(M + H).sup.+                                            4 6-Br --CH.sub.2 CH.sub.2 CH.sub.3 Gum c                                        MS(CI.sup.+):459/461(M + H).sup.+                                        __________________________________________________________________________     Footnotes                                                                     a Purified by chromatography using ethyl acetate/hexane as eluant.            b Purified by chromatography using ethyl acetate as eluant.                   c Purified by chromatography using methanol/dichloromethane as eluant.   

EXAMPLE 20 2-(2-(2-Phenethyl)-4-bromophenoxymethyl)-5-pyridinecarboxylicAcid

A solution of methyl2-(2-(2-phenethyl)-4-bromophenoxymethyl)-5-pyridinecarboxylate (1.82 g,4.27 mmol) in ethanol (16 ml) and THF (8 ml) was treated with 2N NaOH (5ml). The reaction mixture was stirred at ambient temperature for 24hours. The reaction mixture was partially evaporated and diluted with H₂O. The pH of the reaction mixture was adjusted to approximately 4-5 withglacial acetic acid. The precipitate was filtered, washed with water anddried. Recrystallization from ethanol/water gave the title compound as awhite solid (1.78 g, quantitative) m.p. 197-199° C.

NMR: (200 MH₂ ; DMSO-d₆): δ13.4 (bs, 1H), 9.08 (m, 1H), 8.32 (dd, 1H),7.62 (d, 1H), 7.25 (m, 7H), 6.98 (d, 1H), 5.28 (s, 2H), 2.90 (m, 4H).

The starting material was prepared as follows:

A solution of methyl 2-methyl-5-pyridinecarboxylate (10 g, 66.2 mmoles)in CCl₄ (120 ml) was treated with acetic acid (5 ml) followed byN-bromosuccinimide (66 mmol, 11.8 g). The reaction was heated to refluxover a bright lamp and held at reflux for 2 hours. The mixture wasfiltered and the filtrate washed with H₂ O (x1), NaHCO₃ (x1) and brine(x1). The organic phase was dried (MgSO₄) and evaporated to give aresidual red oil which was purified by chromatography (eluant: CH₂ Cl₂/hexane) to give 2-bromomethyl-5-pyridinecarboxylate (2.2 g, 14%).

NMR (250 MH₂, DMSO-d₆): δ9.04 (m, 1H), 8.30 (dd, 1H), 7.70 (dd, 1H),4.74 (s, 2H), 3.89 (s, 3H).

A solution of the 4-bromo-2-(2-phenethyl)phenol (1.25 g, 14.5 mmol inDMF (10 ml) was treated with K₂ CO₃ (0.82 g, 5.96 mmol) and methyl2-bromomethyl-5-pyridine carboxylate (1.14 g, 4.96 mmol). The reactionwas stirred at ambient temperature and then evaporated in vacuo. Theresidue was partitioned between ethyl acetate/H₂ O and the combinedorganic extracts were washed with at NaCl solution, dried (MgSO₄) andevaporated. The residue was purified by chromatography (eluant: ethylacetate/hexane) to give methyl 2-(2-phenethyl)-4-bromophenoxymethyl)-5-pyridinecarboxylic acid (1.82 g, 95%).

NMR: (200 MH₂, DMSO-d₆): δ9.1 (d, 1H), 8.36 (dd, 1H), 7.65 (d, 1H), 7.25(m, 7H), 6.99 (d, 1H), 5.28 (s, 2H), 3.90 (s, 3H), 2.9 (m, 4H).

EXAMPLE 21

The compounds of Table XI were prepared from the appropriate ester andphenol using a similar method to that of example 20.

                  TABLE XI                                                        ______________________________________                                        5  STR69##                                                                      R         m.p. (° C.)                                                                       MS            Footnote                                 ______________________________________                                        5-OH    227-228    (CI.sup.+):350(M + H).sup.+                                                                   a                                            5-H 184-185 (CI.sup.+):334(M + H).sup.+ a                                     5-OMe 182-184 (+veFAB):364(M + H)+ a                                          4-CN 192-194 (CI.sup.+):359(M + H).sup.+ --                                   6-CN 146.4-148.8 (-veFAB):357(M - H).sup.- a                                  6-Br 136.4-137.5 (CI.sup.+):412/414(M + H).sup.+ a                          ______________________________________                                         Footnote                                                                      a Recrystallised from ethanol/water.                                     

EXAMPLE 22 Preparation of3-[6-isopropyl-2-(2-phenethyl)phenoxymethyl]benzoic acid

A solution of methyl3-[6-isopropyl-2-(2-phenethyl)phenoxymethyl]benzoate (2.368 g, 608 mmol)in ethanol (10 ml) was treated with 1N NaOH (13 ml). The reactionstirred at ambient temperature overnight and then partially evaporatedand diluted with water. Acetic acid was added to precipitate the productwhich was filtered, washed with water, and dried to give the titleproduct as a sticky solid (2.01 g, 88%).

NMR (250 MH₂ ; DMSO-d₆): δ8.07 (bs, 1H), 7.91 (m, 1H), 7.58 (m, 1H),7.42 (t, 1H), 7.16 (m, 8H), 4.73 (s, 2H), 3.39 (m, 1H), 2.88 (bs, 4H),1.19 (d, 6H).

EXAMPLE 23

The compounds of table XII were prepared from the appropriate methylester using a similar method to that of example 22.

                  TABLE XII                                                       ______________________________________                                        6  STR70##                                                                      Compound                                                                      No. R M.P. (° C.) and MS Footnote                                    ______________________________________                                        1       4-Br     m.p. 162-163;     a                                              MS(+veFAB):413/411(M + H).sup.+                                             2 4-OCH.sub.3 m.p. 129-130; a                                                   MS(+veFAB):363(M + H).sup.+                                                 3 6-CN m.p. 119.3-120.5; --                                                     MS(+veFAB):358(M + H).sup.+                                                 4 6-Br m.p. 88.4-93.1; a                                                        MS(+veFAB):433/435(M + Na).sup.+                                          ______________________________________                                         Footnote                                                                      a Recrystallised from ethanol/water.                                     

EXAMPLE 24 Preparation ofN-(2-hydroxyethyl)-3-[2-(2-phenethyl)-6-bromophenoxymethyl]benzamide

To a cooled solution (5° C.) of ethanolamine (0.06 g, 1 mmole) andtriethylamine (0.101 g, 1 mmole) in dichloromethane (10 ml) was added asolution of 3-[2-(2-phenethyl)-6-bromophenoxymethyl]benzoyl chloride[0.79 mmole] in dichloromethane [33 ml)]. The reaction was allowed towarm to ambient temperature over 1 hour. The reaction mixture wasevaporated and the residue purified by chromatography (methanol/CH₂ Cl₂)to give the title product as a white solid (0.18 g, 50%), m.p.82.2-84.2° C. MS (FAB+): 454/456 (M+H)⁺.3-[2-(2-phenethyl)-6-bromophenoxymethyl]benzoyl chloride was preparedaccording to the method described in example 9b).

EXAMPLE 25

The compounds of Table XIII were prepared using a similar method to thatof example 24.

                                      TABLE XIII                                  __________________________________________________________________________    1  STR71##                                                                       -                                                                                                 m.p. (°C.) MS and                                 Compound R.sup.1 R elemental analysis (EA) Footnote                         __________________________________________________________________________    1     6-iPr                                                                             --CH.sub.2 CH.sub.2 OH                                                                     MS (+veFAB): 418 (M + H).sup.+                                                                   a                                        EA:                                                                           found: 76.2% C, 7.7% H, 3.2% N                                                calc: 0.4% H.sub.2 O: 76.3% C, 7.5% H, 3.3% N.                              - 2 6-iPr                                                                                                            2  MS (CI.sup.+): 465 (M +                                                    H).sup.+ Gum b                         - 3 6-iPr                                                                                                            3  MS (CI.sup.+): 465 (M +                                                    H).sup.+ Gum b                         - 4 6-iPr --CH.sub.2 CH.sub.2 CH.sub.3 MS (CI.sup.+): 416 (M +                                                       H).sup.+ b                               EA:                                                                           found: 80.8% C, 8.0% H, 3.5% N                                                calc: 80.9% C, 8.0% H, 3.37% N                                             5 not used                                                                     - 6 6-Br                                                                                                             4  MS (CI.sup.+): 501/503 (M +                                                H).sup.+ EA: found: 66.4% C,                                                  4.8% H, 4.9% N calc: 66.4% C,                                                 5.0% H, 5.5% N b                       - 7 6-Br --CH.sub.2 CH.sub.2 CH.sub.3 MS (EI.sup.+): 451/453 (M°                                              ).sup.+ b                                m.p. 76.4-77.2                                                             8 6-CN --CH.sub.2 CH.sub.2 OH MS (CI.sup.+): 401 (M + H).sup.+ a                                                          m.p. 102.9-103.6                   - 9 6-CN                                                                                                             5  MS (CI.sup.+): 448 (M +                                                    H).sup.+ m.p. 95.9-98.1 a                                                       - 10 4-Br --CH.sub.2 CH.sub.2                                               CH.sub.3 MS (CI.sup.+): 452 (M                                                + H).sup.+ c                             m.p. 127-129                                                               11 4-Br --CH.sub.2 CH.sub.2 OH MS (CI.sup.+): 454 (M + H).sup.+ c                                                         m.p. 110-112                       - 12 4-Br                                                                                                            6  MS (CI.sup.+): 501 (M +                                                    H).sup.+ m.p. 126-127 c                                                         - 13 4-OCH.sub.3 --CH.sub.2                                                 CH.sub.2 CH.sub.3 MS (CI.sup.+):                                               404 (M + H).sup.+ c                     m.p. 95-97                                                                 14 4-OCH.sub.3 --CH.sub.2 CH.sub.2 OH MS (CI.sup.+): 406 (M + H).sup.+                                                c                                        m.p. 116-118                                                                - 15 4-OCH.sub.3                                                                                                     6  MS (CI.sup.+): 452 (M +                                                    H).sup.+ m.p. 91-93 c               __________________________________________________________________________     Footnotes                                                                     a Purified by chromatography using methanol/dichloromethane as eluant and     triturating the product with ethyl ether.                                     b Purified by chromatography using methanol/dichloromethate as eluant.        c Purified by chromatography using ethyl acetate/hexane as eluant.       

EXAMPLE 26

Not used

EXAMPLE 27 Preparation of4-(4-carboxy-2-(2-phenethyl)phenoxymethyl)benzoic Acid

To a solution of ethyl ⁴ -hydroxy-3-(2-phenethyl)benzoate (1.04 g, 3.85mmol) in DMF (16 ml) was added K₂ CO₃ (0.94 g, 6.8 mmol) and methyl4-bromomethylbenzoate (1.25 g, 5.5 mmol). The reaction was stirred atambient temperature 18 hours, then evaporated at reduced pressure. Theresidue was partitioned between ethyl acetate and water and the organicphase dried (MgSO₄) and evaporated to give methyl4-(4-ethoxycarbonyl-2-(2-phenethyl)phenoxymethyl)benzoate as a whitesolid after chromatography (eluant: ethyl ether/hexane) (1.2 g, 75%).

NMR (200 MHz, DMSO-d₆): δ8.0 (d, 2H), 7.79 (m, 2H), 7.62 (d, 2H), 7.18(m, 6H), 5.32 (s, 2H), 4.26 (q, 2H), 3.87 (s, 3H), 2.89 (m 4H), 1.30 (t,3H).

The above diester (1.2 g, 2.87 mmol) was dissolved in ethanol (10 ml)and THF (10 ml) and 3N NaOH (10 mL) added. The reaction was allowed tostir at ambient temperature for 2 days. The reaction was partiallyevaporated, diluted with water and acidified to pH4 with dilute HCl. Theprecipitate was filtered, washed with water, and dried to give the titleproduct (0.66 g, 61%).

NMR (250 MHz, DMSO-d₆): δ12.7 (bs, 1H), 8.0 (d, 2H), 7.79 (m, 2H), 7.6(d, 2H), 7.18 (m, 6H), 5.3 (s, 2H), 2.9 (m, 4H).

EXAMPLE 28

Preparation of 4-(2-(2-phenethyl)phenoxymethyl)-2-hydroxybenzoic Acid

A solution of 2-hydroxy-4-methylbenzoic acid (20.0 g, 0.132 mol) inmethanol (200 ml) was cooled in an ice bath. Concentrated, H₂ SO₄ (20ml) was added cautiously and the reaction heated to reflux and held atreflux for 48 hours. The reaction was allowed to cool to ambienttemperature, the solvent evaporated and the residue purified bychromatography (eluant: CH₂ Cl₂) to give methyl2-hydroxy-4-methylbenzoate (19.76 g, 90%).

NMR (200 MHz, DMSO-d₆): δ10.47 (s, 1H), 7.64 (d, 1H), 6.78 (m, 2H), 3.86(s, 3H), 2.3 (s, 3H).

A solution of methyl 2-hydroxy-4-methylbenzoate (19.7 g, 0.119 mole) inpyridine (15 ml) was treated with acetic anhydride (15 ml, 16.23 g,0.158 mol). The reaction was stirred at ambient temperature overnightand then the solvent evaporated. The residue was dissolved in CH₂ Cl₂and the solution washed with 2N aqueous HCl, water, saturated aqueousNaHCO₃ solution, dried (MgSO₄) and evaporated to give methyl2-acetoxy-4-methylbenzoate which was used without further purification(24.58 g, 99%).

NMR: (250 MHz, DMSO-d₆): δ7.84 (d, 1H), 7.21 (m, 1H), 7.04 (bs, 1H),3.28 (s, 3H), 2.38 (s, 3H), 2.26 (s, 3H).

A solution of methyl 2-acetoxy-4-methylbenzoate (24.5 g, 0.118 mole) incarbon tetrachloride (700 ml) was treated with N-bromosuccinimide (20.96g, 0.118 mole), benzoyl peroxide (0.5 g, catalytic) and AIBN (0.03 g).The reaction mixture was heated to reflux, held at reflux for 1 hour andthen allowed to cool to ambient temperature, filtered and evaporated togive methyl 2-acetoxy-4-bromomethylbenzoate which was used withoutfurther purification (34 g, 63% of mixture is desired product).

A solution of 2-(2-phenethyl)phenol (2.0 g, 10 mmol) in DMF (20 ml) washeated with K₂ CO₃ (2.8 g, 20 mmol) and methyl2-acetoxy-4-bromomethylbenzoate (5.1 g, 12.3 mmol). The reaction wasstirred at ambient temperature for 48 hours, then partitioned betweenethyl acetate and water. The organic phase was washed with water (3×),dried (MgSO₄) and evaporated. The residue was purified by chromatography(eluant: ethyl/hexane) to give4-(2-(phenethyl)phenoxymethyl)-2-acetoxybenzoate (1.78 g, 44%).

NMR (200 MHz, DMSO-d₆): δ7.98 (d, 1H), 7.46 (m, 1H), 7.22 (m, 8H), 6.95(m, 2H), 5.21 (s, 1H), 3.82 (s, 3H), 2.86 (m, 4H), 2.28 (s, 3H).

The product from previous step (1.54 g, 3.81 mmol) was dissolved inethanol (20 ml) and THF (15 ml) and 1N aqueous NaOH, (7.6 ml) was added.The reaction was stirred at ambient temperature for 30 hours then thesolvent partially evaporated and diluted with water. Acetic acid wasadded dropwise until no further precipitation was observed. The solutionwas extracted with ethyl acetate (2×) and the organic phase dried(MgSO₄) and evaporated. The residue was purified by chromatography(eluant: methanol/CH₂ Cl₂) to give the title product (0.59 g, 44%), m.p.124.2-126° C.

NMR (200 MHz, DMSO-d₆): δ7.78 (d, 1H), 7.2 (m, 7H), 6.95 (m, 4H), 5.12(s, 2H) , 2.88 (m, 4H).

EXAMPLE 29

4-(2-(2-Phenethyl)-6-bromophenoxymethyl)-2-hydroxybenzoic acid wasprepared from 6-bromo-2-(2-phenethyl)phenol and2-acetoxy-4-bromomethylbenzoate using a similar method to that ofExample 28, m.p. 124.8-133° C.; MS -ve FAB: 425/427 [M-H]-

EXAMPLE 30

Preparation of 4-(2-benzyl-6-bromophenoxymethyl)benzoic acid: Methyl4-(2-benzyl-6-bromophenoxymethyl)benzoate (prepared below) was dissolvedin ethanol (50 ml) and THF (15 ml) and treated with a solution of sodiumhydroxide (1N, 32 ml). The reaction was stirred for 72 hours, partiallyevaporated and the residue diluted with water and acidified with ethylacetate to give a precipitate. The precipitate was recrystallised fromethanol/water to give the title product. MS (CI⁺): 397(M+H)⁺ Elementalanalysis: Calc: 63.5%C, 4.31%H Found: 63.3%C, 4.3%H

The methyl 4-(2-benzyl-6-bromophenoxymethyl)benzoate used above wasprepared as follows:

A solution of 2-bromophenol (4.7 g, 27.2 mmol) in toluene (50 ml) wastreated with benzaldehyde (3.75 g, 35.3 mmol), phenylboronic acid (3.98g, 32.6 mmol) and trichloroacetic acid (1.33 g, 8.1 mmol). The mixturewas heated to reflux and held at reflux for 18 hours. The reactionmixture was then evaporated and the residue subjected to chromatographyto give the boronic acid complex of the adduct which was used in thesubsequent step without further purification.

Borane-tert-butylamine complex (8.51 g, 97.8 mmol) was added to asuspension of AlCl₃ (6.5 g, 48.8 mmol) in dichloromethane (20 ml), at 0°C. The mixture was stirred for 0.75 hours, at 0° C., to give a finewhite suspension. The boronic acid complex (prepared above) indichloromethane (10 ml) was then added and the mixture allowed to warmto ambient temperature and to stir overnight. Hydrochloric acid (1N) wasadded dropwise until pH1 was achieved. A white precipitate appearedtransiently. The mixture was extracted with dichloromethane (×2), theorganic phase dried (MgSO₄) and evaporated and the residue purified bychromatography eluting with ethyl ether/hexane to give2-benzyl-6-bromophenol (3.58 g, 50%) as an oil. MS(CI⁺):262(M⁺).

A solution of 2-benzyl-6-bromophenol (3.2 g, 12.2 mmol) in DMF (50 ml)was treated with K₂ CO₃ (2.19 g, 15.9 mmol) and methyl4-bromomethylbenzoate (3.21 g, 14.02 mmol). The reaction was stirred atambient temperature overnight, filtered and partitioned between ethylacetate and water. The organic phase was washed with water (4×), dried(MgSO₄) and evaporated to give methyl4-(2-benzyl-6-bromophenoxymethyl)benzoate (5.96 g), which was usedwithout further purification. MS(CI⁺):411(M+H)⁺

EXAMPLE 31 4-[2-(2-Phenethyl)phenoxyethyl]benzoic Acid

A solution of methyl 4-[2-(2-phenethyl)phenoxyethyl]benzoate (0.44 g,1.2 mmol) in methanol (20 ml) and THF (5 ml) was treated with NaOH (1N,5 ml). The reaction was heated to reflux for 4 hours. The reaction wasevaporated at reduced pressure. The residual solution was acidified topH1 with 1N HCl. The acidic solution was extracted with ethyl acetate,dried over MgSO₄ and evaporated to give the title compound as a viscousoil (0.29 g, 67%).

Elemental analysis: Calc for C₂₃ H₂₂ O₃ : 79.7% C 6.40%H Found: 77.7% C6.50%H Calc for C₂₃ H₂₂ O₃.O5H₂ O: 77.8% C 6.5%H

NMR (200MH₂, DMSO-d₆), δ1.6 (d, 3H), 2.9 (m, 4H), 5.57 (q, 1H), 6.78 (m,2H), 7.15 (m, 7H), 7.53 (d, 2H), 7.9 (d, 2H).

The starting material was prepared as follows:

4-ethyl benzoic acid (5.0 g, 26.7 mmol) was dissolved in methanol (40ml) and treated with concentrated H₂ SO₄ (0.5 ml). The reaction washeated at reflux for 24 hours. The reaction was evaporated at reducedpressure, partitioned between ethyl acetate/H₂ O. The aqueous layer waswashed with ethyl acetate (1×). The organic phases were combined, washedwith H₂ O, dried over MgSO₄ and evaporated. The material was usedwithout further purification in the subsequent transformation.

A solution of methyl 4-ethyl benzoate (5.4 g, 33.3 mmol) in CCl₄ (200ml) was treated with N-bromosuccinimide (5.93 g, 33.3 mmol). The mixturewas treated with benzoylperoxide (0.1 g). The reaction was heated toreflux for 2 hours. After cooling the reaction mixture was filtered andevaporated to obtain 8.1 g of pale yellow oil (quantitative).

This material was used without purification in the subsequent step.

NMR (200 MHz DMSO-d₆): δ2.0 (d, 3H), 3.90 (s, 3H), 5.54 (q, 1H), 7.65(d, 2H), 7.77 (d, 2H).

2-(2-Phenethyl)phenol (1.5 g 7.6 mmol) was dissolved in DMF (5 ml). Thesolution was treated with K₂ CO₃ (2.2 g, 16 mmol) and methyl4-(1-bromoethyl)benzoate (2.0 g, 8.3 mmol). The reaction was allowed tostir for 60 hours at room temperature then heated to 90° C. for 4 hours.The reaction was partitioned between ethyl acetate/H₂ O. The aqueouslayer was washed with ethyl acetate (1×). The combined organic layerswere washed with H₂ O (4×), dried over MgSO₄ and evaporated.Purification by chromatography (ethyl acetate/hexane) gave 1.99 g ofmethyl 4-[2-(2-phenethyl)phenoxymethyl]benzoate as a colourless oil(73%).

NMR (DMSO d6/200 MHz): δ1.58 (d, 3H), 2.9 (m, 4H), 3.83 (s, 3H), 5.59(q, 1H), 6.77 (t, 2H), 6.96-7.33 (m, 7H), 7.57 (d, 2H), 7.95 (d,.2H). MSCI⁺ :360 (M⁺)

Reference Example 1 Methyl4-[6-methyl-2-(2-phenethyl)phenoxymethyl]benzoate

A mixture of 2-(2-phenethyl)-6-methylphenol (0.59 g 2.78 mmol), methyl4-bromomethylbenzoate (0.96 g 4.21 mmol) and potassium carbonate (0.59g) in DMF (30 ml) was stirred under argon at ambient temperature for 48hours. The reaction mixture was diluted with water (50 ml) and extractedtwice with ethyl acetate (50 ml each time). The ethyl acetate extractswere dried (MgSO₄) and the residue obtained on removal of the solventwas subjected to chromatography on silica, eluting with a mixture ofethyl acetate and hexane (1:50 v/v) to give methyl4-[6-methyl-2-(2-phenethyl)phenoxymethyl]benzoate (0.95 g; 94%). MS(CI⁺):378 (M+NH₄)⁺

Reference Example 2

A similar method to that outlined in Reference Example 1, except usingthe appropriately substituted phenol in place of2-(2-phenethyl)-6-methylphenol, was used to prepare the compounds ofTable XV.

                                      TABLE XV                                    __________________________________________________________________________    1  STR78##                                                                       -                                                                                              Reaction   Equivalents                                      Compound   time Equivalents of bromo                                          No. R                                                                        x- (hours) of K.sub.2 CO.sub.3 compound MS Footnotes                         __________________________________________________________________________    1     6-OMe  --CH.sub.2 CH.sub.2--                                                                18   1.2   1.2   CI.sup.+ : 377 (M + H).sup.+                                                              b, c                           2 6-Cl " 18 1.5 1.5 +veFAB: 381 (M + H).sup.+ b, h                            3 5-Cl " 60 1.3 1.1  a, f                                                     4 5-MeO " 72 1.3 1.1  a, f                                                    5 5-Me " 48 1.3 1.1  a, f                                                     6 6-NO.sub.2 " 18 1.5 1.5 EI.sup.+ : 389 (M°).sup.+ b, h                                                               7 5-Br " 60 1.3 1.1  c,                                                      e                              8 4-CO.sub.2 Et " 18 1.5 1.2  c, f, j                                         9 4-CONEt.sub.2 " 18 1.3 1.1  c, f                                            10 4-CH.sub.2 OH " 18 1.5 1.2  c, f                                           11 4-Cl " 18 1.5 1.1  c, f                                                    12 4-COCH.sub.3 " 18 1.5 1.2  c, f                                            13 4-SMe " 18 1.3 1.1  c, f                                                   14 4-Br " 18 1.3 1.1  c, e, i                                                 15 4-NO.sub.2 " 48 1.3 1.1  c, f                                              16 4-OCH.sub.3 " 24 1.3 1.1  c, f                                             17 4-CH.sub.3 " 18 1.3 1.1  c, f                                              18 4-hexyl " 24 1.3 1.1  b, f                                                 19 4-OCOtBu " 24 1.3 1.1  b, f                                                20 4-CHO " 18 1.3 1.1  b, f                                                   21 6-iPr " 18 1.5 1.5 (CI.sup.+): 406 (M + NH.sub.4).sup.+ b, g                                                               22 6-Br " 60 1.3 1.3                                                         (CI.sup.+): 442 (M +                                                          H).sup.+ b, f                  23 6-Ph " 48 1.3 1.2 (CI.sup.+): 440 (M + NH.sub.4).sup.+ a, f                24 6-hexyl " 60 1.5 1.1 (CI.sup.+): 431 (M + H).sup.+ b, f                    25 6-CHO " 18 2.0 1.1 (EI.sup.+): 374 (M.sup.+) b, f                          26 6-SMe " 18 2.0 1.3 (CI.sup.+): 393 (M + H).sup.+ b, f                      27 6-CONEt.sub.2 " 18 2.0 1.0 (+ve FAB): 446 (M + H).sup.+ b, g                                                               28 not used                   29 6-Br --CH═CH-- 60 2.0 1.1 (+ve FAB): 423 (M + H).sup.+ b, f                                                            30 4-Me, 6-Br --CH.sub.2                                                      CH.sub.2-- 18 2.5 1.1                                                        (EI.sup.+): 438 (M').sup.                                                     + b                            31 4-Br, 6-Br " -- 2.5 1.1 (CI.sup.+): 471 (M.sup.+  + MeOH).sup.+ b, f       32 4-Cl, 6-Me " 18 21.2 1.1 (EI.sup.+): 394 (M').sup.+ d, f                   33 4-F, 6-Br " 18 2.5 1.1 (CI.sup.+): 433 (M + H).sup.+ b, f                  34 4,6-ditBu " 18 2.5 1.1 (EI.sup.+): 458 (M.sup.1).sup.+ b, f                35 4-Me, 6-OMe " 72 1.5 1.22  c, f                                            36 4-OMe, 6-Br " 18 1.5 1.24  c, f                                            37 4-Me, 6-tBu " 18 1.5 1.24  c, f                                            38 4,6-tBu " 18 1.5 1.24  c, f                                                39 4-Br " 18 1.3 1.1  c, e                                                    40 5-OCOtBu " 48 1.3 1.1  a, f                                                41 H " 48 1.1 1.3  a, k                                                     __________________________________________________________________________     Footnotes                                                                     a The reaction mixture was evaporated at reduced pressure. The residue wa     partitioned between ethyl acetate/water. The organic extract was washed       with brine, dried (MgSO.sub.4) and evaporated.                                b The reaction mixture was partitioned between ethyl acetate/water. The       organic phase was washed well with water (4x), dried (MgSO.sub.4) and         evaporated.                                                                   c The reaction mixture was filtered and then evaporated at reduced            pressure. The residue was partitioned between ethyl acetate/water. The        organic phase was washed with brine, dried (MgSO.sub.4) and evaporated.       d The reaction mixture was filtered and then partitioned between ethyl        acetate/water. The organic phase was washed well with water (4x), dried       (MgSO.sub.4) and evaporated.                                                  e Used subsequent step without further purification                           f Purified by chromatography using diethylether/hexane as eluant.             g Purified by chromatography using ethyl acetate/hexane as eluant.            h Purified by chromatography using dichloromethane/hexane as eluant.          i See reference example 24 for preparation of phenol.                         j Starting phenol prepared as per reference example 42 a)                     k Phenol prepared according to JACS 81 2795 (1959)                       

Reference Example 3

Not used.

Reference Example 4 Methyl 4-[5-t-butylcarbonyloxy- (2-phenethyl)phenoxymethyl]benzoate

Triethylamine (5 ml) was added to a stirred suspension of2,4-dihydroxybenzaldehyde (12 g) in dichloromethane (50 ml) at -8° C. Tothis mixture was added t-butylcarbonyl chloride (4.4 ml) and the mixturewas allowed to warm to ambient temperature and was stirred at thistemperature for 16 hours. The reaction mixture was washed consecutivelywith aqueous 1N hydrochloric acid (20 ml), water (20 ml) and saturatedaqueous sodium bicarbonate solution (20 ml) and then dried (MgSO₄). Theresidue obtained on removal of the solvent was subjected tochromatography on silica eluting with a mixture of ethyl acetate andhexane (1:9 v/v) to give 4-(t-butylcarbonyloxy)-2-hydroxy-benzaldehyde(5.82 g; 35%).

The 5-(t-butylcarbonyloxy)-2-(2-phenethenyl)phenol was prepared byreaction of 4-(t-butylcarbonyloxy)-2-hydroxybenzaldehyde withbenzyltriphenylphosphonium bromide using a similar method to thatdescribed in Reference Example 12.

The 5-(t-butylcarbonyloxy)-2-(2-phenethyl)phenol was prepared byhydrogenation of 5-(t-butylcarbonyloxy)-2-(2-phenethenyl)phenol asdescribed in Reference Example 8.

The methyl 4-[5-t-butylcarbonyloxy-2-(2-phenethyl)phenoxy-methyl]benzoate was prepared from 5-(t-butylcarbonyloxy)-2-(2-phenethyl)phenoland methyl 4-bromomethylbenzoate as described in Reference Example 1.

Reference Example 5 4-[4-Bromo-2-(2-phenethyl)phenoxymethyl]benzonitrile

The 4-[4-bromo-2-(2-phenethyl)benzonitrile used as starting material inExample 5 was prepared by reacting 4-bromo-2-(2-phenethyl)-phenol and4-bromomethylbenzonitrile under similar conditions to those described inReference Example 1.

Reference Example 6

The compounds of Table XVI were prepared by reacting4-bromomethylbenzonitrile with the appropriate phenol using a similarmethod to that described in Reference Example 5.

                                      TABLE XVI                                   __________________________________________________________________________    2  STR79##                                                                       - Equivalents                                                                of: Reaction                                                                     Bromo      Time                                                            R Compound K.sub.2 CO.sub.3 (Hours) Footnote MS                             __________________________________________________________________________    4-hexyl                                                                            1.1   1.5  60    d, f  --                                                  4-OH 1.1 1.33 24 c, f --                                                      4-Cl 1.1 1.5 18 d, f --                                                       4-OCH.sub.3 1.1 1.3 72 d, e --                                                6-iPr 1.3 1.3 18 b, g (CI.sup.+): 373 (M + NH.sub.4).sup.+                    6-Ph 1.2 1.3 48 a, f (CI.sup.+): 390 (M + H).sup.+                            6-Br 1.1 2.0 18 b (CI.sup.+): 392 (MH).sup.+                                  6-hexyl 1.1 1.5 48 b, f (CI): 398 (MH).sup.+                                  H 1.1 1.3 48 b, g EI.sup.+  313 (M).sup.+                                     5-Cl 1.1 1.3 48 d, g --                                                       5-OCH.sub.3 1.1 1.3 48 a, c, e --                                           __________________________________________________________________________     Footnotes                                                                     a Evaporate                                                                   b Extract                                                                     c Extract and extract                                                         d Evaporate and extract                                                       e The product was used in the subsequent step without further purificatio     f Purified by chromatography using dichloromethane/hexane as eluant           g Purified by chromatography using diethyl ether/hexane as eluant        

Reference Example 7

The t-butyl esters used as starting material in Examples 3 and 4 wereprepared from the appropriately substituted 2-(2-phenethyl)-phenols andt-butyl 4-bromomethylbenzoate (Tilley et al J Med Chem 34 1125-36(1991)) using a similar method to that described in Reference Example 1.

                  TABLE XVII                                                      ______________________________________                                        1  STR80##                                                                       -   Equivalents                                                              of:                                                                                Bromo                                                                    R Compound K.sub.2 CO.sub.3 Time Data Footnotes                             ______________________________________                                        6-CO.sub.2 Me                                                                        --        --      --   (+veFAB): 469                                                                          a, d                                         [M + Na].sup.+                                                            6-CHO 2.65 2.0  -- (EI.sup.+): 416 a, d                                           (M°).sup.+                                                         4-CO.sub.2 Me 1.2  1.33 72 -- c, e                                          ______________________________________                                         Footnotes                                                                     a Extracted                                                                   b Evaporated                                                                  c Evaporated then extracted                                                   d Purified by chromatography using diethyl ether/hexane as eluant             e Purified by chromatography using ethyl acetate/hexane as eluant        

Reference Example 8 5-Methyl-2-(2-phenethyl)phenol

A solution of (E)-5-methyl-2-(2-phenethenyl)phenol (1.1 g) in ethanol(80 ml) containing 10% palladium/carbon as catalyst (200 mg) washydrogenated at atmospheric pressure. The catalyst was removed byfiltration through acid washed silica and the filtrate concentrated togive 5-methyl-2-(2-phenethyl)phenol as a gum (yield 1.1 g).

Reference Example 9

The compounds of Table XVIII were prepared from the appropriate olefinusing a similar method to that described in Reference example 8.

                  TABLE XVIII                                                     ______________________________________                                        2  STR81##                                                                       -  R                    Footnotes                                          ______________________________________                                        4-CH.sub.3             b                                                        4-OCH.sub.3 b                                                                 4-CO.sub.2 Et (benzyl ether) j, k                                             4-CONEt.sub.2 (benzyl ether)                                                  4-CO.sub.2 Me (benzyl ether) a                                                4-OCOtBu                                                                      4,6-di-t-Bu e, g                                                              4-Me, 6-OMe                                                                   4-Me, 6-tBu c, e                                                              5-OCOtBu                                                                      5-MeO                                                                         6-Cl                                                                          6-MeO                                                                       ______________________________________                                         Footnotes                                                                     a methanol was used as the solvent instead of ethanol                         b reaction time under 4 hours                                                 c reaction time 48 hours                                                      d purified from ethyl acetate/hexane                                          e purified from ethyl ether/hexane                                            f purified by chromatography using diethyl ether/hexane as eluant             g MS (EI+): 310 (M°).sup.+ -                                           h MS (CI.sup.+): 283 (M + H).sup.+ -                                          i m.p. 45.5-46° C.                                                     j used to prepare 4COOH and 4CH.sub.2 OH compounds                            k the starting material was prepared according to reference example           44a)-d)                                                                  

Reference Example 10 2-(2-Phenethyl)-6-nitrophenol

A solution of 2-(2-phenethenyl)-6-nitrophenol (6.82 g) in a mixture ofethanol (200 ml) and toluene (200 ml) containing Wilkinson's catalyst(tris(triphenylphosphine)rhodium(I)chloride) (638 mg) was hydrogenatedat 50° C. at a pressure of 50 atmospheres for 13 hours. The catalyst wasremoved by filtration and the filtrate was evaporated to dryness to give2-(2-phenethyl)-6-nitrophenol (5.38 g; 78%) which was used in subsequentreactions without further purification.

Reference Example 11

The compounds of Table XIX were prepared from the appropriate olefinusing a similar method to that of Reference example 10.

                                      TABLE XIX                                   __________________________________________________________________________    3  STR82##                                                                       -                                                                          Compound     Pressure                                                                          Time                                                           No. R (bar) (hours) MS Footnotes                                            __________________________________________________________________________    1     6-Br   50  24  (CI).sup.+ : 442 (M + H).sup.+                                                             a                                             2 4-SMe 50 18  a                                                              3 4-Cl 50 18  a                                                               4 4,6-di-F 60 24  b                                                           5 4,6-di-Br 50 24 (EI): 353 (M°)+ a                                    6 4-OCH.sub.3, 6-Br 60 24  a                                                  7 4-F, 6-Br 50 24 (CI): 294 (M + NH.sub.4  + H.sub.2 O).sup.+ a                                                8 4-Cl, 6-Me 50 18 (EI.sup.+): 246                                           (M°).sup.+ c                           9 4-Me, 6-Br 50 24 (EI.sup.+): 290 (M°).sup.+ a                        10 5-Br 50 18  a                                                            __________________________________________________________________________     Footnotes                                                                     a purified by Chromatography using diethyl ether/hexane as eluant             b used in subsequent step without further purification                        c purified by Chromatography using dichloromethane as eluant             

Reference Example 12

E 5-Methyl-2-(2-phenethenyl)phenol was prepared as follows:

A solution of lithium bis(trimethylsilyl)amide in THF (37 ml of a 1Nsolution) was added to a stirred suspension ofbenzyltriphenylphosphonium bromide (8.76 g) in THF (60 ml) at ambienttemperature under argon and the mixture was stirred for 45 minutes. Asolution of 4-methyl-2-hydroxybenzaldehyde (made from 4-methylsalicylicacid by the procedure described in reference example 53a)-b)) (2.4 g) inTHF (15 ml) was added and the reaction mixture stirred for 16 hours. Thereaction mixture was partitioned between water (100 ml) and diethylether (100 ml). The aqueous phase was extracted once with diethyl etherand the combined extracts were dried (MgSO₄). The oil obtained onremoval of the solvent was subjected to chromatography on silica, with amixture of ethyl acetate and hexane (1:4 v/v) to give (E)5-methyl-2-(2-phenethenyl)phenol (1.1 g; 26%).

Reference Example 13

The compounds of Table XX were prepared from the appropriate aldehydeusing a similar method to that of Reference example

                                      TABLE XX                                    __________________________________________________________________________    1  STR83##                                                                       -                                                                                       Equivalents                                                        Compound  of phosphonium Equivalents Reaction                                 No. R salt of base time MS Footnotes                                        __________________________________________________________________________    1     5-MeO  1.14    2.3   72                                                                              hours           b                                  2 6-Cl 2.23 2.27 18 hours  b                                                  3 6-MeO 1.1 2.2 5 days  b                                                     4 6-NO.sub.2 1.5 2.2 48 hours  b                                              5 4-Me, 6-tBu 1.14 2.5 72 hours  a                                            6 4-Me, 6-OMe 1.14 2.33 3 days  a, d                                          7 4,6-di-tBu 1.10 2.2 48 hours (CI.sup.+): 309 (M + H).sup.+ a                8 4-OMe, 6-Br 1.14 2.4 4 days  a, f                                           9 4,6-di-Br 1.10 2.1 48 hours (EI).sup.+ : 353 (M°).sup.+ a                                                        10 4-F, 6-Br 1.10 2.1 48                                                     hours (CI.sup.+): 292                                                         (M°).sup.+ a                11 4-Cl, 6-Me 1.10 2.1 18 hours (EI.sup.+): 244 (M°).sup.+ a                                                       12 4-Me, 6-Br 1.10 2.1 48                                                    hours (CI.sup.+): 288 (M +                                                    NH.sub.4--H.sub.2 O).sup.+ a       13 4,6-di-F 1.10 2.2 48 hours  a                                              14 not used                                                                   15 6-hexenyl 1.10 2.2 3 days (CI.sup.+): 276 (M + H).sup.+ a                  16 6-Br 1.10 2.2 4 days (CI.sup.+): 276 (M + H).sup.+ a                       17 4-hexenyl 1.10 2.2 4 days  a                                               18 4-OMe 1.14 2.3 4 days  a                                                   19 4-CH.sub.3 1.15 2.3 3 days  a                                              20 4-SMe 1.10 2.2 3 days  a                                                   21 4-Cl 1.00 2.1 18 hours  b                                                  22 4-OCOtBu 1.10 2.2 18 hours  b                                              23 5-Br 1.15 2.3 5 days  a, e                                               __________________________________________________________________________     Footnotes                                                                     a purified by Chromatography using diethyl ether/hexane as eluant             b purified by Chromatography using ethyl acetate/hexane as eluant             c purified by Chromatography using dichloromethane/hexane as eluant           d starting material prepared according to the method described in JCS         Perkin II (1980), 354 and JCS (1941), 548                                     e for preparation of starting material see Kobayashi, Azekaura Morita,        Chem Pharm Bull (Japan), 17, 89-93, (1969                                     f starting material prepared according to JCS 1998 (1925)                

Reference Example 14 3,5-Dibromo-2-hydroxybenzaldehyde

Hexamine (3.35 g, 23.92 mmol) was added portionwise to trifluoroaceticacid (25 ml) keeping the temperature below 40° C. with a water bath.2,4-Dibromophenol was then added slowly and the reaction mixture heatedat 80° C. for 31/2 hours. The reaction mixture was cooled, partiallyevaporated and then poured into ice/water. This mixture was stirred atambient temperature overnight and the precipitate that formed filtered,dried and purified by chromatography (CH₂ Cl₂ /hexane) to give the titlecompound (2.1 g).

MS (CI)⁺ :279 [M+H]⁺ NMR: (250 MHz, DMSO-d₆):

Reference Example 15

The compounds of Table XXI were prepared from the appropriate phenolusing a similar method to that of Reference example

                  TABLE XXI                                                       ______________________________________                                        2  STR84##                                                                      Compound            Reaction time                                                                          Stir time                                        No. R (hours) (hours) Footnotes                                             ______________________________________                                        1       4-F, 6-Br 31/2       24      a                                          2 4-Me, 6-Br 4 24 b, c, e                                                     3 4-Me, 6-tBu 31/2  48 d                                                    ______________________________________                                         Footnotes                                                                     a Isolated by filtering                                                       b Isolated by extraction with ethyl acetate                                   c Purified by Chromatography using diethyl ether/hexane as eluant             b Purified by Chromatography using hexane as eluant                           e MS (CI.sup.+): 215/217 (M + H).sup.+-                                  

Reference Example 16 3-Bromo-2-hydroxybenzaldehyde

Over 0.25 hours 2-bromophenol (22.38 g, 129 mmol) was added to asolution of Mg(OMe)₂ in methanol (111.9 ml, 8% w/w) and toluene (35 ml).The reaction was heated to reflux and maintained at reflux for 1 hour,then toluene (118 ml) was added. The solvent was distilled off until thetemperature reached 92-94° C. A solution of paraformaldehyde in toluenewas added portionwise over 1 hour at 80-90° C. and the reaction mixtureheated to reflux and maintained at reflux for 3 hours. The reactionmixture was then allowed to cool to ambient temperature and left tostand overnight. Toluene (140 ml) was added to the reaction mixture,which was then washed with 2M H₂ SO₄ (140 ml). The organic phase wasdried and evaporated and the crude material used in the next stepwithout further purification.

MS (CI⁺):201 [M+H]⁺

Reference Example 17

The compounds of table XXII were prepared from the appropriate phenolusing a similar method to that of Reference example

                  TABLE XXII                                                      ______________________________________                                        3  STR85##                                                                       -                  Reaction time                                             Compound  Step 1; Step 2  Foot-                                               No. R (hours) MS note                                                       ______________________________________                                        1       4,6-di-t-Bu                                                                             1.25; 3    (CI.sup.+): 235 (M + H).sup.+                                                            a                                       2 4-Cl, 6-Me 1.5; 3 (EI.sup.+): 170 (M°).sup.+ a                       3 6-hexenyl 2; 3 (CI.sup.+): 205 (M + H).sup.+ a                              4 4-hexenyl 1; 3  a                                                           5 4-SMe 1; 3  a                                                               6 not used                                                                    7 4,6-diF 1; 3.5 (CI.sup.+): 159 (M + H).sup.+ b                            ______________________________________                                         Footnote                                                                      a Purified by Chromatography using diethyl ether/hexane as eluant             b Purified by Chromatography using dichloromethane/hexane as eluant      

Reference Example 18 Ethyl 2-bromomethyl-5-thiazolecarboxylate

A solution of ethyl 2-methyl-5-thiazole carboxylate [S. H Mashragui, P.M. Keehn, JACS 104 4461-4465 (1982)] (4.73 g, 27.68 mmol) in carbontetrachloride (30 ml) was treated with N-bromosuccinimide (4.92 g, 27.64mmol) and benzoyl peroxide (0.03 g). The reaction mixture was heated toreflux under a strong light for 11/4 hours. The reaction was allowed tocool to ambient temperature and filtered. The filtrate was evaporatedand subjected to chromatography (CH₂ Cl₂) to give the title product(1.16 g, 17%). NMR (200 MH₂,DMSO-d₆) : δ8.4 (s, 1H) , 5.06 (s, 2H) ,4.33 (g, 2H), 1.3 (t, 3H).

Reference Example 19 Methyl4-[4-Cyano-2-(2-phenethyl)phenoxymethyl]benzoate

a) A solution of methyl-4-[4-bromo-2- (2-phenethyl)phenoxy-methyl]benzoate (4.0 g) in DMF (120 ml) containing cuprous cyanide (2.08 g)was stirred and heated under reflux for 24 hours in an atmosphere ofargon. The reaction mixture was allowed to cool and was added to asolution of 1,2-diaminoethane (120 ml) in water (600 ml). The mixturewas extracted four times with diethyl ether (150 ml each time), washedwith brine (100 ml) and evaporated to dryness. Toluene (100 ml) wasadded to the residue and the mixture evaporated to dryness. The residuewas subjected to chromatography on silica, eluting with a mixture ofdiethyl ether and hexane (1:3 v/v) to givemethyl-4-[4-cyano-2-(2-phenethyl)phenoxymethyl]benzoate (3.3 g; 94%).

b) The starting material was prepared as follows:

Tetrabutylammonium tribromide (10.00 g) was added to a solution of2-(2-phenethyl)phenol (3.77 g) in dichloromethane (140 ml) at ambienttemperature and the mixture stirred for 2 hours. The reaction mixturewas washed consecutively with aqueous sodium thiosulphate solution(2×100 ml), water (3×100 ml) and brine (100 ml) and then dried (MgSO₄).Removal of the solvent gave an oil which was subjected to chromatographyon silica, eluting with a mixture of ethyl acetate and hexane (1.9 v/v),to give as an oil 4-bromo-2-(2-phenethyl)phenol (4.5 g; 85%).

The methyl 4-[4-bromo-2-(2-phenethyl)phenoxymethyl]benzoate was preparedby reaction of 4-bromo-2-(2-phenethyl)phenol with methyl4-bromomethylbenzoate using a similar method to that described inReference Example 1.

Reference Example 20

The compounds of Table XXIII were prepared from the bromo compound usinga similar method to that of Reference example 19a).

                  TABLE XXIII                                                     ______________________________________                                        4  STR86##                                                                       -         Position of                                                                            Reaction Time       Foot-                                 R --CO.sub.2 Me (hours) MS note                                             ______________________________________                                        5-CN     1        20         CI.sup.+ : 372 (M + H)+                                                                  b                                       6-CN 1 18 CI.sup.+ : 372 (M + H).sup.+ c                                      4-OMe, 6-CN 1 20 -- a                                                         4-Me, 6CN 1 18 CI.sup.+ : 385 (M.sup.+).sup.+ c                               6-CN 2 4 CI.sup.+ : 372 (M + H).sup.+ c                                     ______________________________________                                         Footnotes                                                                     a 2.47 equivalents of CuCN used                                               b 2.5 equivalents of CuCN used                                                c 2.6 equivalents of CuCN used                                           

Reference Example 21

Preparation of methyl 4-[4-bromo-6-cyano-2-(2-phenethyl-phenoxymethyl]benzoate and methyl 4-[6-bromo-4-cyano-2-(2-phenethyl-phenoxymethyl]benzoate:

To a solution of methyl 4-[4,6-dibromo-2-(2-phenethyl-phenoxymethyl]benzoate (0.92 g, 1.82 mmole) in DMF (30 ml) was added CuCN (0.188 g,21. mmol). The reaction was heated at reflux (under argon) for 20 hours.

The reaction was cooled, poured into a solution of ethylene diamine (30ml) in ice water (120 ml). The aqueous solution was extracted with ethylacetate (3×60 ml). The combined organic extracts were washed with brine(2×), dried (MgSO₄) and evaporated. The residue was purified bychromatography (diethyl ether/hexane) to give the title compounds;4-bromo-6-cyano compound (0.127 g) and 4-cyano-6-bromo compound (0.104g).

4-bromo-6-cyano compound:

NMR (200 MHz, DMSO-d₆) δ: 8.02 (d, 2H), 7.98 (s, 1H), 7.85 (d, 1H), 7.6(d, 2H), 7.16 (m, 5H), 5.19 (s, 2H), 3.88 (s, 3H), 2.84 (m, 4H).

4-cyano-6-bromo compound:

NMR (200 MHz, DMSO-d₆) δ: 8.14 (d, 1H), 8.02 (d, 2H), 7.85 (d, 1H), 7.65(d, 2H), 7.18 (m, 5H), 5.07 (s, 2H), 3.89 (s, 3H), 2.87 (m, 4H).

Reference Example 22 Preparation of 6-cyano-2-(2-phenethyl)phenol

A solution of 6-bromo-2-(2-phenethyl)phenol (8.0 g, 28.88 mmol) in DMF(60 ml) was treated with K₂ CO₃ (10.0 g, 72.46 mmol) and benzyl bromide(3.78 ml, 5.44 g, 31.79 mmol). The reaction was stirred for 3 hours atambient temperature then filtered and evaporated. The residue waspartitioned between ethyl acetate/water and the organic phase washedwith H₂ O (4×), dried (MgSO₄) and evaporated to give benzyl6-bromo-2-(2-phenethyl)phenyl ether as an oil. (11.86 g [crude]). MS(EI) :366 (M)⁺.

Benzyl 6-bromo-2-(2-phenethyl)phenyl ether (10.57 g, 28.8 mmol) wasdissolved in DMF (100 ml). Cuprous cyanide (6.72 g, 75 mmol) was addedand the reaction heated to 150° C. for 18 hours. The reaction was pouredin ethylene diamine (440 ml) and water (1.5 l) and the product wasextracted with ethyl acetate (3×). The organic extracts were combined,dried (MgSO₄) and evaporated. The residue was purified by chromatography(diethyl ether/hexane) to give benzyl 6-cyano-2-(2-phenethyl)phenylether as a solid (7.23 g, 80%). MS (CI⁺): 314 (M+H)⁺.

Benzyl 6-cyano-2-(2-phenethyl)phenyl ether (4.86 g, 15.5 mmol) wasdissolved in ethanol (100 ml). The solution was treated with 10% Pd onCarbon (500 mg). The reaction was placed under an atmosphere of hydrogenand allowed to react with vigorous stirring for 2.5 hours. The reactionmixture was filtered through Celite and evaporated. The residue waspurified by chromatography (diethyl ether/hexane) to give the titleproduct (2.86 g, 83%). MS (CI⁺): 224 [M+H]⁺.

Reference Example 23 6-Methyl-2-(2-phenethyl)phenol

A solution of 1-(2-benzyloxy-3-methylphenyl)-2-phenylethene (2.19 g) inethanol (50 ml) containing 10% palladium on charcoal as catalyst washydrogenated at atmospheric pressure. The reaction mixture was filteredthrough acid washed silica and the residue obtained on concentration ofthe filtrate was subjected to chromatography on silica, eluting with amixture of ethyl acetate and hexane (1:50 v/v) to give6-methyl-2-(2-phenethyl)phenol (0.66 g; 42%; m.p. 45.5-46° C.).

Using this same procedure there was obtained

    ______________________________________                                        1  STR87##                                                                           Compound No.                                                                           R                                                             ______________________________________                                               1        5-Cl                                                          ______________________________________                                    

The 1-[(2-benzyloxy-3-methyl) phenyl]-2-phenylethene used as startingmaterial was prepared as follows:

A solution of lithium bis(trimethylsilyl)amide in THF (15.8 ml of a 1Nsolution) was added to a stirred suspension of benzyltriphenylphosphonium bromide (6.84 g) in THF (40 ml) and the mixturestirred under argon for 30 minutes. A solution of2-benzyloxy-3-methylbenzaldehyde (2.38 g) (prepared from2-hydroxy-3-methylbenzoic acid according to Reference example 29a)-c));in THF (15 ml) was added to the reaction mixture and stirring continuedfor 48 hours. The reaction mixture was quenched with water (50 ml) andextracted three times with ethyl acetate (50 ml each time). The ethylacetate extracts were dried (MgSO₄) and the residue obtained on removalof the solvent was subjected to chromatography on silica, eluting withan ethyl acetate/hexane mixture (1:100 v/v) to give1-[(2-benzyloxy-3-methyl)phenyl]-2-phenylethene (2.47 g; 78%) as amixture of E and Z isomers. MS (CI⁺) (M+NH₄)⁺ 318; (M+H)⁺ 301.

This method was used to prepare1-(2-benzyloxy-4-chlorophenyl)-2-phenylethene as a gum;2-benzyloxy-4-chlorobenzaldehyde was prepared according to Referenceexample 29a)-c).

Reference Example 24 Preparation of 4-bromo-2-(2-phenethyl)phenol

Tetrabutylammonium tribromide (10.00 g) was added to a solution of2-(2-phenethyl)phenol (3.77 g) in dichloromethane (140 ml at ambienttemperature and the mixture stirred for 2 hours. The reaction mixturewas washed consecutively with aqueous sodium thiosulphate solution(2×100 ml), water (3×100 ml) and brine (100 ml) and then dried (MgSO₄).Removal of the solvent gave an oil which was subjected to chromatographyon silica, eluting with a mixture of ethyl acetate and hexane (1.9 v/v),to give as an oil 4-bromo-2-(2-phenethyl)phenol (4.5 g; 85%).

The 2-(2-phenethyl)phenol was prepared according to the route describedin the literature JACS, 81, 2795, (1959).

Reference Example 25 Preparation of methyl4-(2-(2-phenethyl)-6-hydroxy-phenoxymethyl)benzoate

A suspension of 2,3-dihydroxybenzaldehyde (15 g, 109 mmole) in CH₂ Cl₂(70 ml) was cooled to -10° C. Triethyl amine (5.49 g, 54.3 mmol) wasadded followed by pivaloyl chloride (6.49 g, 53.9 mmol). The reactionwas allowed to stir for 1 hour at -10° C. and then warmed to ambienttemperature. The reaction mixture was stirred at ambient temperatureovernight, then washed with water, 1N aqueous HCl, saturated aqueousNaHCO₃ and water. The organic phase was dried (MgSO₄) and evaporated.The residue was purified by chromatography (eluant: ethylacetate/hexane) to give 2-hydroxy-3-pivaloyloxybenzaldehyde: (10.15 g,84%).

NMR (200 MHz, DMSO-d₆): δ10.78 (s, 1H), 10.15 (s, 1H), 7.64 (dd, 1H),7.38(dd, 1H), 7.05 (t, 1H), 1.32 (s, 9H).

To a solution of 2-hydroxy-3-pivaloyloxybenzaldehyde (1.0 g, 4.5 mmole)in DMF (5 ml) was added Na₂ CO₃ (0.859 g, 8.10 mmol) and methyl4-bromomethylbenzoate (1.13 g, 4.93 mmol). The reaction was stirred atambient temperature for 60 hours then partitioned between ethylacetate/H₂ O. The organic phase was washed with water (x1) dried (MgSO₄)and evaporated to give methyl4-(2-formyl-6-pivaloyloxy-phenoxymethyl)benzoate as a product which wasused in subsequent steps without further purification.

NMR (200 MHz, DMSO-d₆): δ10.12 (s, 1H), 7.97 (d, 2H), 7.67 (dd, 1H),7.54 (m, 3H), 7.36 (t, 1H), 5.18 (s, 2H), 3.86 (s, 3H), 1.26 (s, 9H).

LiN(SiMe₃)₂ [1N in THF, 17.2 ml] was added to a suspension of benzyltriphenylphosphonium bromide (7.45 g, 17.2 mmol) in THF (80 ml). Thereaction was stirred for 30 minutes at ambient temperature. A solutionof methyl 4-(2-formyl-6-pivaloyloxyphenoxymethyl)benzoate (3.183 g, 8.59mmole) in THF (20 ml) was added keeping the temperature below 40° C. Thereaction was stirred at ambient temperature for 18 hours then treatedwith water, neutralised with dilute aqueous HCl and extracted with ethylacetate. The organic phase was dried (MgSO₄) and evaporated. The residuewas purified by chromatography (eluant: ethyl acetate/hexane) to givemethyl 4-(2-(2-phenethenyl)-6-hydroxyphenoxymethyl)benzoate (1.68 g,55%).

NMR (200 MHz, DMSO-d₆) (mixture of cis and trans isomers): δ9.52 (bs,1H), 7.96 (m, 2H), 7.62 (m, 2H), 7.45 to 6.4 (complex multiplets, 10H)(two singlets together, 2H), 5.08 and 5.07 (two singlets together, 3H),3.86 and 3.85 (two singlets together, 3H).

A solution of methyl4-(2-(2-phenethenyl)-6-hydroxyphenoxy-methyl)benzenecarboxylate (1.39 g,3.87 mmol) in ethanol (50 ml) and toluene (50 ml) was treated withWilkinson's catalyst (0.15 g). The reaction was hydrogenated at 50° C.and 50 bar for 18 hours, then evaporated. The residue was purified bychromatography (eluant: ethyl acetate/hexane) to give methyl4-(2-(phenethyl)-6-hydroxyphenoxy-methyl)benzoate: (1.12 g, 80%).

NMR (200 MHz, DMSO-d₆): δ9.40 (bs, 1H), 7.98 (d, 2H), 7.6' (d, 2H), 7.14(m, 5H), 6.85 (t, 1H), 6.76 (dd, 1H), 6.66 (dd, 1H), 5.01 (s, 2H), 3.87(s, 3H), 2.56 (bs, 4H).

Reference Example 26 Preparation of6-(N-diethylcarbamoyl)-2-(2-phenethyl)phenol

To a suspension of hexane washed NaH (60% in mineral oil, 0.16 g, 4mmol) in THF (5 ml) was added to a solution of6-bromo-2-(2-phenethyl)phenol (1.0 g, 3.6 mmol) in THF (5 ml). Thereaction was stirred at ambient temperature for 45 minutes then cooledto -70° C. A solution of n-butyl lithium (1.6M in hexane, 4.62 ml, 7.4mmol) was added keeping the temperature below -55° C. The reactionmixture was stirred at -70° C. for 1.25 hours then poured onto crushedsolid CO₂ in THF. The reaction was allowed to warm to ambienttemperature, acidified with dilute HCl and extracted with ethyl acetate.The organic phase was dried (MgSO₄) and evaporated to give2-hydroxy-3-(2-phenethyl)benzoic acid. The crude material was usedwithout further purification in the subsequent step (0.805 g).

The crude 2-hydroxy-3-(2-phenethyl)benzoic acid (0.805 g 3.33 mmol) wasdissolved in CH₂ Cl₂ (15 ml) and treated with oxalyl chloride (0.55 ml,0.8 g, 6.3 mmol) and 2 drops of DMF. The reaction was stirred at ambienttemperature for 1 hour, then evaporated The residue was dissolved in CH₂Cl₂ (15 ml), evaporated and dissolved in dichloromethane (4 ml).

The acid chloride solution was added to a stirred solution of diethylamine (1.19 g, 16.3 mmol) in dichloromethane (10 ml). The reactionmixture turned a deep green/brown colour. After 30 minutes the reactionwas evaporated and the residue purified by chromatography (eluant:methanol/CH₂ Cl₂) to give 6-(N-diethyl-carbamoyl)-2-(2-phenethyl)phenol(0.314 g, 32%).

NMR (200 MHz; DMSO-d₆): δ9.0 (bs, 1H), 7.23 (m, 5H), 7.09 (dd, 1H), 6.95(dd, 1H), 6.78 (t, 1H), 3.31 (m, 4H), 2.85 (bs, 4H), 1.07 (t, 6H).

Reference Example 27 Preparation of 6-methylthio-2-(2-phenethyl)phenol

To a suspension of hexane washed NaH (60% in mineral oil, 0.238 mg, 5.95mmol) in THF (4 ml) was added to a solution of6-bromo-2-(2-phenethyl)phenol (1.5 g, 5.4 mmol) in THF (4 ml). Thereaction was stirred for 30 minutes at ambient temperature, then cooledto -70° C. A solution of n-butyl lithium (1.6M in hexane, 3.72 ml, 5.95mmol) was added keeping the temperature below -65° C. The reaction wasstirred at -70° C. for 30 minutes and Me₂ S₂ (0.25 g, 2.6 mmoles) added.The reaction temperature rose to -50° C. and was allowed to warm toambient temperature. The reaction mixture was partitioned between ethylacetate/dilute aqueous HCl, the organic phase was dried (MgSO₄) andevaporated and the residue purified by chromatography (eluant ethylether/hexane) to give a 1:1 mixture of 6-bromo and6-methylthio-2-(2-phenylethyl)phenol. (1.29 g, 98%). Ms (CI⁺): 2.5 [M⁺H]⁺ [6-SMe].

The mixture was alkylated using a similar method to that of ReferenceExample 1 and purified by chromatography (eluant: ethyl ether/hexane togive methyl 4-(2-(2-phenethyl)-6-methylthio phenoxy-methyl)benzoatecleanly.

NMR (200 MH₂, DMSO-d₆): δ8.01 (d, 2H), 7.64 (d, 2H), 7.18 (m, 8H), 4.93(s, 2H), 3.87 (s, 3H), 2.85 (bs, 4H), 2.42 (s, 3H).

Reference Example 28 Preparation of methyl4-(6-amino-2-(2-phenethyl)phenoxy-methyl)benzoate

A solution of methyl 4-(6-nitro-2-(2-phenethyl)phenoxy-methyl)benzoate(1.5 g, 3.84 mmol) in ethyl acetate (20 ml) was treated with stannouschloride (4.34 g, 19.2 mmole). The reaction was heated to 70° C. for 5hours, then allowed to cool to ambient temperature. The reaction mixturewas partitioned between ethyl acetate/water and the organic phase dried(MgSO₄) and evaporated. The residue was purified by chromatography(eluant: ethyl acetate/hexane) to give the title product (0.946 g, 68%).

NMR (200 MH₂, DMSO-d₆): δ9.99 (dd, 2H), 7.64 (dd, 2H), 7.16 (m, 5R),6.80 (t, 1H), 6.63 (dd, 1H), 6.50 (dd, 1H), 4.86 (s, 2H), 3.87 (s, 3H),2.77 (bs, 4H)

Reference Example 29 Preparation of 6-isopropyl-2-(phenethyl)phenol

A solution of 2-hydroxy-3-isopropylbenzoic acid (5 g, 27.8 mmol) inacetone (40 ml) was treated with K₂ CO₃ (7.67 g, 55.6 mmol) and benzylbromide (9.98 g; 58.4 mmol). The reaction was stirred at ambienttemperature for 60 hours, then evaporated. The residue was partitionedbetween ethyl acetate/H₂ O and the organic phase dried (MgSO₄) andevaporated. The residue was purified by chromatography (eluant: ethylacetate/hexane) to give benzyl 2-benzyloxy-3-isopropylbenzoate (6.52 g,18.11 mmol, 65%)

NMR (200 MHz, DMSO-d₆): δ7.58 (m, 2H), 7.39 (m, 10H), 7.23 (t, 1H), 5.32(s, 2H), 4.86 (s, 2H), 3.30 (m, 1H), 1.14 (d, 6H).

A solution of LiAlH₄ (1M in THF, 8.13 ml) was added to freshly distilledTHF (10 ml) 10 ml. A solution of benzyl 2-benzyloxy-3-isopropylbenzoate(2.27 g, 6.31 mmole) in THF (10 ml) was added via a syringe to theLiAlH₄ solution. The temperature was maintain below 40° C. using a waterbath and the reaction mixture stirred at ambient temperature overnight.The reaction was quenched with water and the pH adjusted to ˜7 withdilute HCl. The resultant precipitate was filtered off and the filtratepartitioned between ethyl acetate/H₂ O. The organic phase was dried(MgSO₄), evaporated and the residue purified by chromatography (eluant:ethyl acetate/hexane) to give 2-benzyloxy-3-isopropylbenzylalcohol (1.38g, 83%).

NMR (200 MHz, DMSO-d₆): δ7.29 (m, 8H), 4.82 (s, 2H), 4.58 (s, 2H), 3.30(m, 1H), 1.17 (d, 6H).

A solution of 2-benzyloxy-3-isopropylbenzyl alcohol (1.26 g, 4.9 mmoles)in chloroform (50 ml) was heated with manganese dioxide (1.92 g, 22mmole). The reaction was stirred at ambient temperature overnight,filtered and evaporated. The residue was purified by chromatography(eluant: ethyl acetate/hexane) to give2-benzyloxy-2-isoproplybenzaldehyde, (0.71 g, 57%).

A suspension of benzyl triphenylphosphonium bromide (1.43 g, 3.3 mmol)in THF (20 ml) was treated with LiN(SiMe₃)₂ [1M in THF, 3.3 ml). Thereaction was stirred at ambient temperature for 30 minutes. A solutionof 2-benzyl-3-isopropyl benzaldehyde (0.56 g, 2.2 mmole) in THF (10 ml)was added and the reaction was stirred at ambient temperature for 48hours. The reaction was partitioned between ethyl acetate/H₂ O and theorganic phase washed well with H₂ O, dried (MgSO₄) and evaporated. Theresidue was purified by chromatography to give2-benzyloxy-1-isopropyl-3-(2-phenethenyl)benzene (0.52 g, 72%).

NMR (200 MHz, DMSO-d₆): (mixture of cis trans isomers) δ7.7 to 6.6(complex multiplets, 15H), 4.90 and 4.85 (two singlets together 2H 3.32(m, 1H), 1.16 (m, 6H).

A solution of 2-benzyloxy-1-isopropyl-3-(2-phenethenyl)-benzene, (0.46g, 1.4 mmol) in ethanol 30 ml was treated with 10% palladium carbon[0.10 g]. The reaction was placed under a hydrogen atmosphere andstirred vigorously until the uptake of hydrogen ceased. The reaction wasfiltered through Celite and evaporated to give2-(2-phenethyl)-6-isopropylphenol (0.34 g, quantitative).

NMR (200 MHz, DMSO-d₆): δ8.1 (s, 1H), 7.23 (m, 5H), 6.99 (dd, 1H), 6.91(t, 1H), 3.31 (m, 1H), 2.63 (bs, 1H), 1.16 (d, 6H).

Reference Example 30 Preparation of 2-(2-phenethyl)-6-phenylphenol

Methanol (50 ml) was treated with concentrated sulphuric acid (4.9 g,2.66 ml) cautiously. 2-Hydroxy-3-phenylbenzoic acid (10.7 g, 50 mmol)was added and the reaction mixture stirred at ambient temperature for 18hours. The mixture was then heated at reflux for 4 hours, cooled toambient temperature and evaporated. The residue was partitioned betweenethyl acetate/and water, the organic layer washed twice with water,dried (MgSO₄) and evaporated to give methyl 2-hydroxy-3-phenylbenzoate.

A solution of methyl 2-hydroxy-3-phenylbenzoate (9.5 g, 41.7 mmol) inDMF (80 ml) was treated with K₂ CO₃ (8.6 g, 62.5 mmole) and benzylbromide (10.6 g 62.2 mmol). The reaction was stirred at ambienttemperature overnight, then partitioned between ethyl acetate/and water.The organic phase was washed well with water, dried (MgSO₄) andevaporated. The residue was purified by chromatography (eluant: ethylacetate/hexane) to give methyl 2-benzyloxy-3-phenylbenzoate (11.23 g,8.5%).

NMR (250 MHz, DMSO-d₆): δ7.72 (dd, 1H), 7.65-7.07 (complex multiplets,10H), 7.06 (m, 2H), 4.53 (s, 2H) 3.82 (s, 3H)

This was reduced with LiAlH₄ using a similar method to that of Referenceexample 29 to give 2-benzyloxy-3-phenylbenzyl alcohol.

2-Benzyloxy-3-phenylbenzyl alcohol was oxidised with manganese dioxideusing a similar method to that described in Reference Example 29 to give2-benzyloxy-3-phenylbenzaldehyde.

2-Benzyloxy-3-phenylbenzaldehyde was reacted with benzyltriphenylphosphonium bromide using a similar method to that of Example48 to give 2-benzyloxy-1-phenyl-3-styrylbenzene, which was hydrogenatedusing a similar method to that of Reference Example 29 to give2-(2-phenethyl)-6-pherylphenol.

Reference Example 31 Preparation of 6-hexyl-2-(2-phenethyl)phenol

To a stirred suspension of pentyl triphenylphosphonium bromide (10.4 g,25.2 mM) in freshly distilled THF (40 ml) was added LiN(SiMe₃)₂ (1M inTHF, 50 ml). The reaction was stirred at ambient temperature for 1 hour.Salicylaldehyde (2.8 g, 22.9 mM) was added to the reaction mixture whichwas stirred at ambient temperature for 60 hours. The reaction was thentreated with water, the pH adjusted with 1N aqueous HCl to pH7 andextracted twice with ethyl acetate. The organic layers were combined,dried over (MgSO₄) and evaporated. The residue was purified bychromatography to give 2-(1-hexenyl)phenol, (3.57 g, 88%).

NMR (200 MHz, DMSO-d₆): δ9.40 (bs, 1H), δ7.32 (dd, 1H), 7.0 (m, 1H),6.72 (m, 3H), 6.19 (m, 1H), 2.18 (m, 2H), 1.38 (m, 4H), 0.90 (m, 3H).

To a stirred solution of Mg(OMe)₂ (8% by weight in methanol 16.88 ml,12.76 mM) was added 2-(1-hexenyl)phenol (3.44 g, 19.5 mmol) in toluene(18 ml). The reaction mixture was warmed to reflux and held at refluxfor 2 hours. Toluene (18 ml) was added and the solvent distilled offuntil the reaction temperature rose to 93° C. A slurry ofparaformaldehyde (1.8 g, 60 mmol) in toluene (18 ml) was added and thereaction heated at reflux for 3 hours. The reaction was allowed to coolto ambient temperature and stirred overnight. The reaction was dilutedwith toluene (20 ml) and washed with 2M aqueous H₂ SO₄ (20 ml). Theorganic phase was washed with water until the aqueous phase was neutralin pH, dried (MgSO₄) and evaporated. The residue was purified bychromatography (eluant: ethyl ether/hexane) to give3-(1-hexenyl)-2-hydroxybenzaldehyde (2.32 g, 58%).

NMR (200 MHz, DMSO-d₆): δ11.35 (s, 1H), 10.02 (s, 1H), 7.77 (d, 1H),7.65 (dd, 1H), 7.04 (t, 1H), 6.67-6.3 (m, 2H), 2.21 (m, 2H), 1.4 (m, 4H), 0.90 (t, 3H)

To a suspension of benzyltriphenylphosphonium bromide (5.25 g, 12.12mmol) in THF (30 ml) was added LiN(SiMe₃)₂ [1N in THF, 24.26 ml]. Thereaction was stirred at ambient temperature for 30 minutes and asolution of 3-(1-hexenyl)-2-hydroxybenzaldehyde (2.25 g, 11.03 mmol) inTHF (5 ml) added. The reaction was stirred at ambient temperature for 60hours, then quenched with water. The pH of the aqueous layer wasneutralised with HCl (1N) and the reaction mixture extracted twice withethyl acetate. The combined organic phases were washed with water, dried(MgSO₄) and evaporated. The residue was purified by chromatography(eluant: ethyl ether/hexane) to give2-(2-phenethenyl)-6-(1-hexenyl)phenol, (2.28 g, 74%).

NMR (200 MHz, DMSO-d₆): (mixture of cis and trans isomers). δ8.9 (bs,1H), 7.83-6.05 (complex multiplets, 12H), 2.2 (m, 2H), 1.38 (m, 4H),0.90 (m, 3H).

To a solution of 6-hexenyl-2-(2-phenethenyl)phenol (2.15 g, 7.73 mmol)in ethanol (30 ml) was added 10% palladium on carbon (0.2 g). Thereaction was placed under an atmosphere of hydrogen and stirred atambient temperature for 18 hours. The reaction mixture was then filteredthrough Celite and evaporated. The residue was purified bychromatography to give 6-hexyl-2-(2-phenethyl)phenol (1.66 g, 7%).

NMR (200 MHz, DMSO-d₆): δ8.1 (s, 1H, 7.2(m, 5H), 6.9 (d, 2H), 6.66 (t,1H), 2.53 (m, 4H), 1.63-0.75 (broad multiplets, 13H).

Reference Example 32 Preparation of methyl4-(6-benzene-2-(2-phenethyl)-sulphonamidophenoxymethyl)benzoate

A stirred solution of methyl4-(6-amino-2-(2-phenethyl)-phenoxymethyl)benzoate (0.553 g, 1.53 mmol)in dichloromethane (5 ml) was treated with pyridine (0.36 g, 4.58 mmol)and benzenesulphonyl chloride (0.346 g, 1.97 mmol). The reaction wasstirred at ambient temperature overnight then partitioned betweendichloromethane and water. The organic layer was washed well with water,dried (Mgso₄) and evaporated. The residue was purified by chromatography(eluant: ethyl ether/hexane) to give the title product (0.53 g, 69%).NMR (200 MHz, DMSO-d₆): δ9.76 (bs, 1H) 7.97 (d, 2H), 7.78 (m, 2H), 7.57(m, 5H), 7.05 (m, 8H), 4.68 (s, 2H), 3.88 (s, 3H), 2.71 (s, 4H).

Reference Example 33 Preparation of2-hydroxy-3-(2-phenethyl)benzaldehyde

To a stirred solution of Mg(OMe)₂ [8% weight in methanol, 21.9 ml 16.47mM) was added, over 5 minutes, a solution of 2-(2-phenethyl)phenol [5.0g, 25.25 mM] in toluene (7 ml). The reaction was then heated to refluxand held at reflux for 1 hour (64° C.), then toluene (23 ml) was addedand the solvent distilled off until the reaction temperature reached 93°C. A suspension of paraformaldehyde (2.35 g, 78.3 mM) in toluene (15 ml)was then added over 10 minutes keeping the reaction temperature at 86°C. The reaction was heated at reflux for 3 hours, then allowed to coolto ambient temperature and to stand for 18 hours. The reaction wasdiluted with toluene (28 ml) and washed with 2M aqueous H₂ SO₄ (27 ml).The organic phase was washed with water until a neutral pH was achieved.After drying (MgSO₄) the solution was evaporated and the residuepurified by chromatography (eluant: ethyl ether/hexane) to give thetitle product (3.11 g, 54%).

NMR (200 MHz, DMSO-d₆): δ11.15 (bs, 1H), 10.03 (s, 1H), 7.63 (dd, 2H),7.44 (dd, 2H), 7.23 (m, 5H), 6.98 (t, 1H), 2.88 (m, 9H).

Reference Example 34 Preparation of methyl4-(6-acetyl-2-(2-phenethyl)-phenoxymethyl)benzoate

A solution of 2-hydroxy-3-(2-phenethyl)benzaldehyde (1.0 g, 4.4 mmol) inTHF (30 ml) was cooled to -78° C. under argon. Methyl lithium (1.4M inethyl ether, 6.6 ml, 9.2 mmol) was added dropwise keeping thetemperature below -60° and the reaction mixture stirred at -70° C. for 1hour. The reaction was allowed to warm to 0° C. and quenched with water,the pH of the mixture was adjusted to neutral with HOAc and it wasextracted with ethyl acetate. The organic phase was dried (MgSO₄) andevaporated. The resulting 6-(1-hydroxyethyl)-2-(2-phenethyl)phenol wasused in the subsequent step (1.1 g quantitative) without furtherpurification.

NMR (250 MHz, DMSO-d₆): δ8.9 (s, 1H), 7.25 (m, 6H), 7.0 (m, 2H), 6.7 (t,1H), 5.94 (bs, 1H), 5.03 (q, 1H), 2.84 (bs, 4H), 1.87 (d, 3H).

A solution of the above hydroxy phenol (0.525 g, 2.17 mmol) in DMF (10ml) was treated with potassium carbonate (0.6 g, 4.35 mmol) and methyl4-bromomethyl benzoate (0.596 g, 2.6 mmol). The reaction was stirred atambient temperature overnight, then partitioned between ethyl acetateand water. The organic phase was washed well with water (4×), brine,dried (MgSO₄) and evaporated. The residue was purified by chromatography(eluant: ethyl ether/hexane) to give methyl4-(6-(1-hydroxyethyl)-2-(2-phenethyl)-phenoxymethyl)benzoate (0.486 g,57%).

NMR (250 MHz, DMSO-d₆): δ8.04 (d, 2H), 7.62 (d, 2H), 7.38 (dd, 1H), 7.14(m, 7H), 5.05 (q, 1H), 4,9 (q, 2H), 3.89 (s, 3H), 2.85 (bs, 4H), 1.33(d, 3H).

A solution of the alcohol from above (0.441 g, 1.13 mmol) in chloroform(10 ml) was treated with manganese dioxide (0.92 g, 10.6 mmol). Thereaction was stirred at ambient temperature for 4 hours, then heated to40° C. and held at 40° C. for 48 hours. The reaction mixture wasfiltered through Celite and evaporated. The residue was purified bychromatography (eluant: ethyl ether/hexane) to give methyl4-(6-acetyl-2-(2-phenethyl)phenoxymethyl)benzoate: (0.268 g, 65%).

NMR (250 MHz, DMSO-d₆ : δ7.99 (d, 2H), 7.57 (d, 2H), 7.5 (d, 2H), 7.15(m, 6H), 4.4 (s, 2H), 3.87 (s, 3H), 2.85 (m, 4H), 2.54 (s, 3H).

Reference Example 35 Preparation of methyl4-(6-(N-diethylamino)-2-(2-phenethyl)phenoxymethyl)benzoate

A stirred solution of methyl4-(6-amino-(2-(2-phenethyl)-phenoxymethyl)benzoate (0.52 g, 1.44 mmol)in DMF (10 ml) was treated with K₂ CO₃ (0.795 g, 5.76 mmol) and ethyliodide (1.79 g, 11.5 mmol). The reaction was heated to 40° C. andstirred at 40° C. for 4 hours, then allowed to cool to ambienttemperature and stirred for 18 hours. The reaction was filtered andpartitioned between ethyl acetate/H₂ O. The organic phase washed withwater (4×), dried (MgSO₄) and evaporated. The residue was purified bychromatography (eluant: ethyl ether/hexane) to give the title product.

NMR (200 MHz, DMSO-d₆): δ7.98 (d, 2H), 7.57 (d, 2H), 7.05 (m, 8H), 5.04(s, 2H), 3.87 (s, 3H), 3.14 (q, 4H), 2.78 (s, 4H), 0.96 (t, 6H).

Reference Example 36 Preparation of methyl2-hydroxy-3-(2-phenethyl)benzoate

A stirred suspension of washed sodium hydride (0.875 g, 60%, 21.87 mmol)in THF (30 ml) was treated with a solution of6-bromo-2-(2-phenethyl)phenol (5.5 g, 19.8 mmol) in THF (20 ml). Thereaction was stirred at ambient temperature for 30 minutes then cooledto -70° C. A solution of n-butyl lithium (1.6M, 26 ml, 41.6 mmol) wasadded, keeping the temperature below -60° C., and the reaction wasstirred at -70° C. for 1 hour. The reaction was poured onto excesscrushed CO₂ in THF and allowed to warm to ambient temperature overnight.The mixture was acidified with aqueous HCl and extracted with ethylacetate. The organic phase was dried (MgSO₄) and evaporated and theresidue purified by chromatography (eluant: methanol/CH₂ Cl₂) to give2-hydroxy-3-(2-phenethyl)benzoic acid (4.29 g, 89%).

NMR (200 MHz, DMSO-d₆): δ7.64 (dd, 1H), 7.2 (m, 6H), 6.63 (t, 1H), 2.64(s, 4H).

A solution of 2-hydroxy-3-(2-phenethyl)benzoic acid (4.43 g, 18.3 mmol)in methanol (50 ml) was treated with concentrated H₂ SO₄ (4 ml). Thereaction was heated to reflux on a steam bath and held at reflux for 18hours, then allowed to cool to ambient temperature and the solventevaporated. The residue was purified by chromatography (eluant: ethylether/hexane) to give the title product (2.94 g, 63%).

NMR (250 MHz, DMSO-d₆): δ10.96 (bs, 1H), 7.66 (dd, 1H), 7.36 (dd, 1H),7.24 (m, 5H), 6.84 (t, 1H), 3.91 (s, 3H), 2.87 (bs, 4H).

Reference Example 37 Preparation of tert-butyl4-(6-cyanomethyl-2-(2-phenethyl)-phenoxymethyl)benzoate

To a stirred solution of tert-butyl4-(6-formyl-2-(2-phenethyl)phenoxymethyl)benzoate (6.32 g, 16.9 mmol) inethanol (100 ml) was added portionwise NaBH₄ (0.879 g, 23.25 mmol). Thereaction mixture became faintly pink. The temperature of the mixture waskept below 30° C. and stirred at ambient temperature for 1.5 hours. Thesolvent was evaporated and ethyl acetate added to the residue. Thissolution was added dropwise to a stirred solution of further 1N aqueousHCl (70 ml) and water (50 ml). The organic phase was washed with water,saturated aqueous sodium hydrogen carbonate and brine, dried (MgSO₄) andevaporated. The residue containing tert-butyl4-(6-hydroxymethyl-(2-(2-phenethyl)phenoxymethyl)benzoate was usedwithout further purification in the subsequent step (6.15 g, 87%).

NMR (250 MHz, DMSO-d₆): δ7.95 (d, 2H), 7.59 (d, 2H), 7.18 (m, 8H), 5.05(t, 1H), 4.9 (s, 2H), 4.57 (d, 2H), 2.83 (s, 4H), 1.58 (s, 9H).

A solution of tert-butyl4-(6-hydroxymethyl-2-(2-phenethyl)-phenoxymethyl)benzoate (0.711 g, 1.7mmol) in dichloromethane (20 ml) was cooled to 0° C. Tetrabromomethane(0.694 g, 2.09 mmol) and triphenylphosphine-polymer bound (1.11 g, 3mmol/g, 3.33 mmol) were added and the reaction was allowed to stir at 0°C. for 1 hour and then allowed to warm to ambient temperature. Thereaction was stirred at ambient temperature for 30 minutes then filteredand evaporated. The residue containing tert-butyl4-(6-bromomethyl-2-(phenethyl)-phenoxymethyl)benzoate was used withoutpurification in the subsequent steps (0.82 g, quantitative).

NMR (200 MHz, DMSO-d₆): δ7.95 (d, 2H), 7.62 (d, 2H), 7.23 (m, 8H), 5.03(s, 2H), 4.7 (s, 2H), 2.87 (s, 4H), 1.57 (s, 9H).

A solution of the containing tert-butyl4-(6-bromomethyl-2-(2-phenethyl)phenoxymethyl)benzoate (0.82 g, 1.71mmol) in DMSO (20 ml) was treated with NaCN (0.208 g, 4.24 mmol). Thereaction was heated to 100° C. for 10 minutes. The reaction mixture waspartitioned between ethyl ether and water and the organic phaseevaporated. The residue was purified by chromatography (eluant: ethylether/hexane) to give the title product (0.277, 38%). NMR (250 MHz,DMSO-d₆): δ7.95 (d, 2H), 7.61 (d, 2H), 7.19 (m, 8H), 4.93 (s, 2H), 4.00(s, 2H), 2.87 (s, 4H), 1.57 (s, 9H).

Reference Example 38 Preparation of tert-butyl4-(6-methoxymethyl-2-(phenethyl)-phenoxymethyl)benzoate

Sodium hydride (0.1 g, 2.27 mmol) was washed with hexane (2×) and thensuspended in THF (10 ml). tert-Butyl4-(6-hydroxymethyl-2-(2-phenethyl)-phenoxymethyl)benzoate was added tothis suspension (0.816 g, 1.95 mmol) as a solution in THF (5 ml). Thereaction was stirred at ambient temperature for 30 minutes (untileffervescence ceased). Methyl iodide (0.55 g, 3.87 mmol) was then addedand the reaction stirred at ambient temperature for 11/2 hours. Theorganic phase was dried (MgSo₄) and evaporated and the residue purifiedby chromatography (eluant: ethyl ether/hexane) to give the titleproduct.

NMR (250 MHz, DMSO-d₆): δ7.95 (d, 2H), 7.58 (d, 2H), 7.18 (m, 8H), 4.92(s, 2H), 4.46 (s, 2H), 3.3 (s, 3H), 2.85 (s, 4H), 1.57 (s, 9H).

Reference Example 39

Preparation of methyl4-(2-(2-phenethyl)-4-phenylthiomethylphenoxymethyl)benzoate

Methyl 4-(4-hydroxymethyl-2-(2-phenethyl)phenoxymethyl)benzoate (0.5 g,1.33 mmol) was dissolved in pyridine (3 ml), cooled to 0° C. (underargon) and treated with PhSSPh (0.87 g, 4 mmol) and tributyl phosphine(0.8 g, 4 mmol). The mixture was allowed to warm to ambient temperatureand stirred at ambient temperature overnight. The reaction waspartitioned between ethyl ether and water and the etherial layer washedwith water (2×), 1N HCl (2×), and brine (1×). The organic phase wasdried (MgSO₄) and evaporated. The residue was purified by chromatography(eluant: ethyl ether/hexane) to give the title product as a white solid(0.43 g).

NMR (250 MHz, DMSO-d₆): δ8.0 (d, 2H), 7.59 (d, 2H), 7.15 (m, 10H), 5.19(s, 2H), 4.15 (s, 2H), 3.88 (s, 3H), 2.8 (m, 4H).

Reference Example 40

The compounds of Table XXIV were prepared using a similar method to thatof Reference Example 39.

                  TABLE XXIV                                                      ______________________________________                                        1  STR88##                                                                      Compound                                                                      No. R R.sup.1 MS                                                            ______________________________________                                        1        --CH.sub.2 SPh                                                                           t-butyl                                                     2 --CH.sub.2 SMe t-butyl FAB.sup.+ : 468 (M + H).sup.+                      ______________________________________                                    

Reference Example 41

Not used.

Reference Example 42 Preparation of 4-hydroxymethyl-2-(2-phenethyl)phenol

a) A solution of the ethyl 4-benzyloxy-3-(2-phenethenyl)benzoate,preparation described in Reference example 44 parts a)-d), (2.6 g, 7.25mmol) in ethanol (40 ml) was treated with 10% palladium on carbon (0.25g). The reaction was placed under an atmosphere of hydrogen and stirredat ambient temperature until the uptake of hydrogen ceased. The reactionwas filtered through Celite and evaporated to give ethyl4-hydroxy-3-(2-phenethyl)benzoate as a colourless gum (2.2 g, 84%).

NMR (250 MHz, DMSO-d₆): δ10.21 (brs, 1H), 7.7-7.1 (complex multiplets,together 7H), 6.89 (m, 1H), 4.24 (q, 2H), 2.84 (s, 4H), 1.28 (t, 3H).

b) To a stirred suspension of LiAlH4 (0.93 g, 24.4 mmol) in freshlydistilled THF (70 ml) under argon was added dropwise ethyl4-hydroxy-3-(2-phenethyl)benzoate (4.4 g, 12.1 mmol) as a solution inTHP (25 ml). Once the addition was complete the reaction was stirred atambient temperature for four hours. Water was added to decompose theexcess LiAlH₄ and the pH was adjusted to pH1-2 by the addition of 1Naqueous HCl. The reaction mixture was extracted with ethyl acetate (2×).The combined extracts were washed with brine, dried (MgSO₄) andevaporated. The residue was purified by chromatography (eluant: ethylacetate/hexane) to give the title product as a colourless solid (1.25 g,45%).

NMR (200 MHz, CDCl₃): δ7.18 (m, 7H), 6.72 (m, 1H), 4.68 (s, 1H), 4.57(m, 2H), 2.91 (s, 4H)

Reference Example 43 Preparation of methyl4-(4-cyanomethyl-2-(2-phenethyl)phenoxymethyl)benzoate

To a stirred solution of the methyl4-(4-hydroxymethyl-2-(2-phenethyl)phenoxymethyl)benzoate (0.5 g, 1,33mmol) in dry CH₂ Cl₂ (16 ml) at 0° C. under argon was addedtetrabromomethane (0.543 g, 1.64 mmol) followed by triphenylphosphinepolymer bound (3 mmol/g) (0.89 g, 266 mmol). The reaction was stirred at0° C. for 1 hour, allowed to warm to ambient temperature and stirred for1 hour. The reaction mixture was filtered to remove the polymer andevaporated to give methyl4-(4-bromomethyl-2-(2-phenethyl)phenoxymethyl)benzoate which was usedwithout further purification.

NMR (250 MHz, DMSO-d₆): δ8.00 (m, 2H), 7.6 (m, 2H), 7.2 (m, 6H), 5.4 (s,2H), 4.65 (s, 2H), 3.87 (s, 3H), 2.9 (m, 4H).

To a solution of the above methyl4-(4-bromomethyl-2-(2-phenethyl)phenoxymethyl)benzoate (1.33 mmol, 0.58g) in DMSO (15 ml) was added sodium cyanide (0.163 g, 3.32 mmol). Thereaction was stirred at ambient temperature for 2 hours and then allowedto stand overnight. The reaction mixture was partitioned between ethylester and water and the aqueous layer was washed with ethyl ether (2×).The combined etherial extracts were washed with brine, dried (MgSO₄) andevaporated. The residue was purified by chromatography to give the titleproduct as an off-white solid (0.2 g, 38%).

NMR (200 MHz, DMSO-d₆): δ8.0 (d, 2H), 7.60 (d, 2H), 7.17 (m, 8H), 5.23(s, 2H), 3.89 (s, 2H), 3.66 (s, 3H), 2.66 (bs, 4H).

Reference Example 44 Preparation of4-(N-diethylcarbamoyl)-2-(2-phenethyl)phenol

A solution of 5-bromo-2-benzyloxybenzaldehyde, prepared from commercial5-bromosalicylicaldehyde by benzylation according to the method given inReference example 22a), (25 g, 74.6 mmol) in toluene (250 ml) wastreated with ethylene glycol (5 ml), and p-toluenesulfonic acid (0.24g). The reaction was heated to reflux with azeotropic removal of water(Dean Stark trap). After 2.5 hrs, no further water was collected. Thereaction was cooled to ambient temperature and washed with saturatedaqueous NaHCO3, dried (MgSO₄ and evaporated to give2-(2-benzyloxy-5-bromophenyl)-1,3-dioxolane as a pale orange solid (26.8g). This material was used without purification.

NMr (200 MHz, DMSO-d₆): 7.42 (m, 7H), 7.08 (m, 1H), 6.03 (s, 1H), 5.18(s, 2H), 3.98 (m, 4H)

b) A solution of 2-(2-benzyloxy-5-bromophenyl)-1,3-dioxolane (7.8 g,23.2 mmol) in freshly distilled THF (160 ml) was cooled to -75° C. withstirring under an argon atmosphere. To this solution was added n-butyllithium (25.6 ml, 1.6 M in hexane) keeping the temperature below -70° C.The reaction mixture was stirred at -70° C. for 1 hour. The reaction wasallowed to warm to -60° C. and added to a cooled (-60° C.) solution ofethyl chloroformate (5.05 g, 46.5 mmol) in freshly distilled THF (70ml). The reaction was allowed to warm to ambient temperature and stirredovernight. The reaction mixture was diluted with ethyl ether (100 ml),washed with ice/water (1×50 ml), saturated aqueous NaHCO3 (1×35 ml),brine (1×35 ml) dried over MgSO4 and evaporated. The product waspurified by chromatography (eluant: ethyl ether/hexane) to give2-(2-benzyloxy-5-ethoxycarbonylphenyl)-1,3-dioxolane as a colourless gum(4.2 g, 55%).

NMR (200 MHz, DMSO-d6): δ8.03 (d, 1H), 7.94 (dd, 1H), 7.42 (m, 6H), 6.05(s, 1H), 5.25 (s, 2H), 4.29 (q, 2H), 4.0 (m, 4H), 1.30 (t, 3H).

c) A solution of the above dioxolane (1.0 g, 3.05 mmol) in ethanol (5ml) and THF (5 ml) was treated with 2N aqueous HCl (3 ml). The reactionwas allowed to stand at ambient temperature overnight then evaporated tolow bulk, treated with ice, water and extracted with ethyl acetate (2×).The combined organic extracts were washed with water, saturated aqueoussodium bicarbonate and brine, dried (MgSO₄) and evaporated to give ethyl4-benzyloxy-2-formylbenzoate as a colourless gum (0.88 g). This materialwas used in the subsequent step without further purification.

NMR (200 MHz, DMSO-d₆): δ10.40 (s, 1H), 8.23 (m, 2H), 7.44 (m, 6H), 5.4(s, 2H), 4.32 (q, 2H), 1.32 (t, 3H).

d) A suspension of benzyl triphenylphosphonium bromide (1.34 g, 31.mmol) in freshly distilled THF (15 ml) was treated with LiN(SiMe₃ )₂ (1Nin THF, 3.7 ml). After stirring for 45 minutes at ambient temperaturethe red solution was treated with a solution of ethyl4-benzyloxy-2-formylbenzoate (0.88 g, 31. mmol) THF (3 ml). The reactionwas stirred at ambient temperature for 24 hours, then partitionedbetween ethyl ether and water. The combined etherial extracts werewashed with brine, dried (MgSO4) and evaporated. The residue waspurified by chromatography (eluant: ethyl ether/hexane) to ethyl4-benzyloxy-3-(2-phenethenyl)benzoate as a colourless gum (0.57

NMR (200 MHz, DMSO-d6): (mixture of cis and trans isomers) δ8.3-6.6(series of complex multiplet taken together 15H), 5.32 and 5.22 (twosinglets, together 2H), 4.3 and 4.15 (two quartets, together 2H), 1.34and 1.19 (two triplets, together 3H).

e) A solution of the above ester (0.57 g, 1.6 mmol) in ethanol (8 ml)and THF (8 ml) was treated with 1N aqueous NaOH (3.5 ml) and allowed tostand at ambient temperature overnight. The reaction was partiallyevaporated, diluted with water, acidified with acetic acid and extractedwith ethyl acetate (2×). The combined extracts were dried (MgSO4) andevaporated to give 4-benzyloxy-3-(2-phenethenyl)benzoic acid as a whitesolid (0.47 g).

f) A suspension of the above acid (0.47 g, 1.4 mmol) in dry CH₂ Cl₂ (10ml) was treated with oxalyl chloride (0.23 g, 1.77 mmol) and 3 drops ofDMF. The reaction was stirred at ambient temperature for 3.5 hours thenthe solvent was evaporated to dryness, the residue taken up in dry CH₂Cl₂ and the solvent evaporated a second time. Finally the acid chloridewas dissolved in dry CH₂ Cl₂ (5 ml). The resultant solution of acidchloride was added to a solution of diethylamine (0.113 g, 1.54 mmol)and triethylamine (0.424 g, 4.2 mmol) in dry CH₂ Cl₂ (5 ml) at ambienttemperature. The reaction mixture was allowed to stand at ambienttemperature overnight and then the solvent was evaporated. The residuewas purified by chromatography (eluant: ethyl ether/hexane HOAc) to giveN,N-diethyl-4-benzyloxy-3-(2-phenethenyl)benzamide as a colourless gum(0.3 g, 56%).

NMR (250 MHz, DMSO-d6): (mixture of cis, trans) δ67.7-6.6 (complexmultiplets, together 15H), 5.26 and 5.2 (2 singlets, together 2H), 3.2(broad multiplet, partially obscured by H₂ O), 1.13 (broad triplet) and0.92 (broad singlet) (together 6H).

g) A solution of the above amide (0.3 g, 0.78 mmol) in ethanol (10 ml)was treated with 10% palladium on carbon (0.03 g). The reaction mixturewas placed under a hydrogen atmosphere, stirred until the uptake ofhydrogen ceased, filtered and evaporated to give4-(N-diethylcarbamoyl)-2-(2-phenethyl)phenol as a colourless gum (0.227g, 98%).

NMR (200 MHz, DMSO-d6): δ9.71 (broad s, 1H), 7.42-7.08 (m, 5H), 7.00 (m,2H), 6.82 (d, 1H), 3.25 (m, partially obscured by H₂ O), 2.83 (s, 4H),1.05 (m, 6H)

Reference Example 45 Preparation of methyl4-(4-hydroxyimino-2-(2-phenethyl)phenoxymethyl)benzoate

Methyl 4-(4-formyl-2-(2-phenethyl)phenoxymethyl)benzoate (0.18 g, 0.48mMol) was dissolved in ethanol (3 ml) and treated with hydroxylaminehydrochloride (0.040 g, 0.57 mMol) and pyridine (0.1 ml). The reactionmixture was refluxed on a steam bath for 3 hours, then allowed to coolto ambient temperature. The resulting precipitate was dissolved in ethylether and the organic solution washed with 2N aqueous HCl (2×), water(1×) and brine (1×). The etherial layer was dried (MgSO4) and evaporatedto give the title product as white solid (0.19 g, quantitative).

NMR D1065 (200 MHz, DMSO-d6): δ11.24 (s, 1H), 8.43 (s, 1H), 8.00 (d,J=8.3 Hz, 2H), 7.65 (m, 3H), 7.21 (m, 5H), 7.02 (m, 1H), 6.88 (m, 1H),5.29 (s, 2H), 3.88 (s, 3H), 3.01 (m, 2H), 2.85 (m, 2H).

Reference Example 46

The compounds of Table XXV were prepared using a similar method to thatof Reference Example 45.

                  TABLE XXV                                                       ______________________________________                                        2  STR89##                                                                      Compound                                                                      No. R MS                                                                    ______________________________________                                        1          4-C(═N--OH)CH.sub.3                                              2 6-C(═N--OH)H (FAB.sup.+): 390 (M + H).sup.+                             3 6-C(═N--OH)CH.sub.3 (FAB.sup.+): 404 (M + H).sup.+                    ______________________________________                                    

Reference Example 47 Preparation of methyl4-(4-methanesulphinyl-2-(2-phenethyl) phenoxymethyl)benzoate

A solution of the methyl4-(4-methylthio-2-(2-phenethyl)phenoxymethyl)benzoate (0.73 g, 1.79mmol) in CH₂ Cl₂ (25 ml) was cooled to -10° C. To this solution wasadded portionwise 3-chloroperoxybenzoic acid (0.586 g, 55%, 1.86 mmol).The temperature of the reaction was maintained below 8° C. Once theaddition of the peracid was complete (2 hours total reaction time) nostarting material could be detected by TLC (ethyl ether/hexane). Thereaction mixture was washed with saturated aqueous NaHCO3, dried (MgSO4)and evaporated. The crude product was purified by chromatography(eluant: ethyl acetate/ethyl ether) to give the title product as a whitesolid (0.55 g, 75%).

NMR (200 MHz, DMSO-d6) : δ8.01 (d, 2H) , 7.63 (d, 2H), 7.46 (m, 2H),7.18 (m, 6H), 5.30 (s, 2H), 3.88 (s, 3H), 2.92 (m, 4H).

Reference Example 48

The compounds of Table XXVI were prepared from the appropriate thiocompound using a similar method to that of Reference Example 47.

                  TABLE XXVI                                                      ______________________________________                                        3  STR90##                                                                      Compound                                                                      No. R R.sup.1 MS                                                            ______________________________________                                        1        6-SOMe     Me        (CI.sup.+): 409 (M + H).sup.+                     2 6-CH.sub.2 SOMe tBu (CI.sup.+): 465 (M + H).sup.+                         ______________________________________                                    

Reference Example 49 Preparation of methyl4-(4-(methylsulphonyl-2-(2-phenethyl)phenoxymethyl)benzoate

A solution of methyl 4-(4-methylthio-2-(2-phenethyl)phenoxymethyl)benzoate (0.77 g, 1.96 mMol) was cooled to 0° C. 3-Chloroperoxybenzoicacid (1.23 g, 55%, 3.92 mmol in 15 ml CH₂ Cl₂ was added keeping thetemperature below 2° C. The reaction was stirred for 30 minutes to 0° C.and then warmed to ambient temperature. The reaction mixture was stirredfor 30 minutes at ambient temperature, then washed with saturatedaqueous NaHCO₃ (2×), dried (MgSO₄) and evaporated. The crude product waspurified by chromatography (eluant ethyl ether/hexane) to give the titleproduct as a white solid (0.45 g, 54%).

NMR (200 MHz, DMSO-d6): δ8.01 (d, 2H), 7.67 (m, 4H), 7.22 (m, 6H), 5.36(s, 2H), 3.87 (s, 3H), 3.08 (s, 3H), 2.92 (m,4H).

Reference Example 50

The compounds of Table XXVII were prepared from the appropriate thiocompound using a similar method to that of Reference Example 49.

                  TABLE XXVII                                                     ______________________________________                                        3  STR91##                                                                      Compound                                                                      No. R R.sup.1 MS                                                            ______________________________________                                        1        6-CH.sub.2 SO.sub.2 CH.sub.3                                                             tBu       (CI.sup.+): 498 (M + NH.sub.4).sup.+                                           2 6-CH.sub.2 SO.sub.2 Ph tBu (FAB.sup.+):                                    565 (M + Na+)                                   ______________________________________                                    

Reference Example 51 Preparation of 4-nitro-2-(2-phenethyl)phenol,6-nitro-2- (2-phenethyl)phenol and 4,6-dinitro-2-(2-phenethyl)phenol

Concentrated nitric acid (2.08 ml, 33 mMol] was added carefully toacetic anhydride (8.4 ml) at 0° C. The mixture was stirred at 0° C. for15 minutes, then 2-(2-phenethyl)phenol (6.2 g, 31.3 mmol in 200 ml ofacetic anhydride) was added at 0° C. Once the addition was complete theyellow solution was allowed to warm to ambient temperature and to standovernight. The reaction mixture was concentrated at reduced pressure andthe residue purified by chromatography (eluant: ethyl ether/hexane) togive 6-nitro-2-(2-phenethyl)phenol (A) (2.4 g) as a bright yellow solid.An orange/yellow solid (3.8 g) was also obtained. This was purified bychromatography (eluant: ethyl acetate/hexane) to give4,6-dinitro-2-(2-phenethyl)phenol (B) (0.70 g) as an orange solid and4-nitro-2-(2-phenethyl)phenol (C) (1.5 g)].

(A): NMR (200 MHz, DMSO-d₆): δ10.54 (s, 1H) , 7.86 (dd, J=1.6, 8.4 Hz,1H), 7.49 (dd, J=1.6, 7.4 Hz, 1H), 7.25 (m, 5H), 6.95 (dd, J=8.4, 7.4Hz, 1H)2.91 (m, 4H).

(B): NMR (200 MHz, DMSO-d₆): δ8.61 (d, J=2.86 Hz, 1H), 8.27 (d, J=2.86Hz, 1H), 7.23 (m, 5H), 3.04 (m, 2H), 2.89 (m, 2H).

(C): NMR (200 MHz, DMSO-d₆): δ11.05 (bs, 1H), 8.00 (m, 2H), 7.25 (m,5H), 6.97 (d, J=9.3 Hz, 1H), 2.88 (bs, 4H).

Reference Example 52 Preparation of 4-hexyl-2-(2-phenethyl)phenol

To a suspension of pentyl triphenylphosphonium bromide (4.76 g, 11.5mMol) in freshly distilled THF (40 ml) was added LiN(SiMe3)₂ (1N in THF,23 ml). The red solution was stirred at ambient temperature for 30minutes then a solution of p-hydroxybenzaldehyde (1.06 g, 10 mMol) inTHF (10 ml) added. The reaction was stirred at ambient temperature for 4days, then partitioned between ethyl ether and dilute aqueous HCl (1N).The combined etherial extracts were washed with brine, dried (MgSO4) andevaporated. The crude oil was purified by chromatography (eluant: ethylether/hexane) to give 4-(1-hexenyl)phenol as a pale yellow solid (1.5 g,85%).

NMR (200 MHz, DMSO-d₆) (mixture of cis and trans isomers): δ9.33 (s,1H), 7.14 (m, 2H), 6.70 (m, 2H), 6.26 (m, 1H), 6.1-5.35 (multiplets,together 1H), 2.35-2.08 (m, 2H), 1.36 (m, 4H), 0.89 (m, 3H).4-(1-Hexenyl)phenol in toluene (8 ml) was added to Mg(OMe)₂ (7.3 ml, 8%wt/wt solution in methanol, 5.5 mMol) and the resultant red solutionheated at reflux for 1 hour. The mixture was then distilled until thereaction temperature rose to 95° C. A suspension of paraformaldehyde(0.78 g, 26 mmol) in toluene (5 ml) was then added and the reactionheated at reflux for three hours. The reaction was allowed to cool toambient temperature and to stir overnight. The reaction mixture was thendiluted with toluene and washed with 2M aqueous H₂ SO₄ (10 ml). Theorganic layer was washed with water (3×), dried (MgSO₄) and evaporated.The residue was purified by chromatography (eluant: ethyl ether/hexane)to give 5-(1-hexenyl)-2-hydroxybenzaldehyde as a yellow/green oil (0.65g, 38%).

NMR (200 (MHz, DMSO-d₆ ): (mixture of cis and trans isomers): δ10.74(bs, 1H), 10.32 and 10.29 (2 singlets, together 1H), 7.66-7.44 (m, 2H),7.02 (m, 1H), 6.5-6.33 (m, 1H), 6.3-5.6 (multiplets, together 1H), 2.24(m, 2H), 1.43 (m, 4H), 0.95 (m, 3H).

To a suspension of benzyl triphenyl phosphonium bromide (4.0 g, 3.5mmol) in freshly distilled THF (20 ml) was added as a solution ofLiN(SiMe₃)₂ (1N, 7.0 ml). The red solution was stirred at ambienttemperature for 45 minutes and then a solution of the aldehyde fromabove, (0.65 g, 3.2 mmol) in THF (8 ml) was added. The resultantreaction was stirred at ambient temperature for 4 days then treated with1N aqueous HCl (10 ml) and extracted with ethyl ether (2×). The combinedextracts were washed with brine, dried MgSO₄ and evaporated. The residuewas purified by chromatography (eluant: ethyl ether/hexane) to give4-(1-hexenyl)-2-(2-phenethyl)phenol as a pale yellow solid (0.5 g, 56%,mixture of cis and trans isomers of both olefins).

NMR (200 MHz, DMSO-d₆): δ9.68 (bs, 1H), 7.55-5.40 (complex multiplets,12H), 2.4-2.0 (m, 2H), 1.33 (m, 4H), 0.85 (m, 3H).

To a solution of 4-(1-hexenyl)-2-(2-phenethenyl phenol (0.5 g, 1.8 mmol)in ethanol (40 ml) was added 10% palladium on carbon of(0.050 g). Thereaction was placed under an atmosphere of hydrogen to stirred at STPuntil the uptake of hydrogen ceased. The reaction was filtered to removecatalyst. The filtrate was evaporated to leave a colourless oil whichwas used without purification (0.5 g, 99%).

NMR (250 MHz, DMSO-d₆ ): δ8.96 (bs, 1H), 7.22 (m, 5H), 6.79 (m, 2H),6.69 (d, 1H), 2.79 (m, 4H), 2.41 (bt, 2H), 1.47 (m, 2H), 1.26 (m, 6H),0.86 (bt, 3H).

Reference Example 53 Preparation of 2-hydroxy-5-methylbenzaldehyde

a) To a suspension of LiAlH₄ (2.5 g, 66 mmol) LiAlH₄ in freshlydistilled THF (8 ml) at 0° C. under argon, was added dropwise withstirring a solution of 5-methylsalicylic acid (5 g, 33 mmol) in freshlydistilled THF (80 ml). Addition was complete in 0.75 hours and thereaction stirred at ambient temperature overnight. Careful addition ofwater (5 ml) was followed by the addition of ice (10 ml) andconcentrated HCl (1 ml). The solvent was decanted and the residuetreated with ethyl ether and ice water. The pH of the mixture wasadjusted to pH 1 with concentrated HCl and the organic layer combinedwith the decanted solvent, washed with brine, dried (MgSO₄) andevaporated. The residue was subjected to chromatography (eluant: ethylether/hexane) to give 2-hydroxymethyl-4-methylphenol as a white solid(3.1 g, 68%).

NMR: (200 MHz, DMSO-d₆): δ8.96 (bs, 1H), 7.06 (bs, 1H), 6.82 (bd, 1H),6.62 (d, 1H), 4.44 (s, 2H), 2.19 (s, 3H).

b) 2-Hydroxymethyl-4-methylphenol (3.1 g, 22.4 mMol) was dissolved inCHCl₃ (95 ml). The solution was treated with manganese dioxide (8.7 g,100 mmol) and the reaction stirred at ambient temperature overnightunder an argon atmosphere. The reaction was then filtered through Celiteand the solvent evaporated. The residue was subjected to chromatography(eluant: ethyl ether/hexane) to give 2-hydroxy-5-methylbenzaldehyde as apale green solid (0.63 g, 20.7%).

NMR (200 MHz, DMSO-d₆): δ10.45 (s, 1H), 10.21 (s, 1H), 7.45 (bs, 1H),7.33 (dd, 1H), 6.89 (d, 1H), 2.45 (s, 3H).

Reference Example 54 Preparation of4-hydroxy-3-(2-phenethyl)benzaldehyde

A solution of 2-(2-phenethyl)phenol (5 g, 25.3 mmol) in drydichloromethane (10 ml) under an argon atmosphere, at -5° C., wastreated with a solution of TiCl₄ in CH₂ Cl₂ (1N, 56.5 ml), maintainingthe temperature below -3° C. (exothermic). To the deep red solution wasadded Cl₂ CHOCH₃ (3.5 g, 30.4 mmol), again maintaining the temperaturebelow -3° C. The reaction was allowed to warm to 0° C. and to stir for 1hour, then the reaction was allowed to warm to ambient temperature andto stir for 2.5 hours. The nearly black reaction mixture was poured ontoice (25 g) and HCl (1 ml) and ethyl ether (50 ml) added. After stirringfor 30 minutes the mixture was extracted with ethyl acetate (2×100 ml)and the combined extracts washed with brine, dried (MgSO₄) andevaporated. The residue was purified by chromatography (eluant: ethylether/hexane) to give the title product (0.18 g) as an off-white solid.

NMR (200 MHz, DMSO-d₆): δ10.27 (s, 1H), 9.34 (s, 1H), 7.81 (dd, 1H),7.58 (dt, 1H), 7.38 (m, 2H), 6.98 (d, 2H), 6.78 (d, 1H), 6.67 (t, 1H),3.25 (m, partially obscured by H₂ O), 2.78 (m, 2H).

Reference Example 55 Preparation of 2-hydroxy-5-pivaloyloxy-benzaldehyde

To a cooled (-8° C.), stirred suspension of 2,5-dihydroxybenzaldehyde(13 g, 93.6 mmol) in of CH₂ Cl₂ (65 ml) (dried over 4A sieves) (65 ml)was added triethylamine (6.5 ml, 46.8 mmol) to give a deep red solution.Pivaloyl chloride (5.6 g, 46.8 mmol) was added portionwise keeping thetemperature below 0° C. After the addition was complete the reaction wasallowed to warm to ambient temperature and stirred overnight. Thereaction was washed with 2N aqueous HCl, water, saturated aqueous NaHCO3and dried (MgSO₄). The organic solution was filtered and evaporated andthe residue purified by chromatography (eluant: CH₂ Cl₂ /hexane) to givethe title product as a colourless oil which crystallized on standing(4.7 g, 45% based on limiting reagent).

NMR (200 MHZ, DMSO-d₆): δ10.74 (bs, 1H), 10.25 (s, 1H), 7.27 (m, 2H),7.02 (d, 1H), 1.29 (s, 9H).

Reference Example 56

Not used.

Reference Example 57 Preparation of tert-butyl4-(4-N-methylcarbamoyl-2-(2-phenethyl)phenoxymethyl)benzoate

A solution of the tert-butyl4-(4-methoxycarbonyl-2-(2-phenethyl)phenoxymethyl)benzoate (1.12 g, 2.5mmol) in THF (10 ml) and t-butanol (10 ml) was treated with 1N aqueousNaOH (10 ml). The reaction was stirred at ambient temperature for 60hours, the solvent partially evaporated, diluted with water andacidified with acetic acid. The mixture was extracted with ethyl acetate(2×) and the combined extracts were washed with brine (2×), dried(MgSO₄) and evaporated to give tert-butyl4-(4-carboxy-2-(2-phenethyl)phenoxymethyl)benzoate as a white solid (1.0g, 93%).

NMR (250 MHz, DMSO-d₆): δ12.5 (very broad singlet, 1H), 7.95 (d, 2H),7.78 (m, 2H), 7.6 (d, 2H), 7.15 (m, 6H), 5.3 (s, 2H), 2.88 (m, 4H), 1.55(s, 9H).

A solution of tert-butyl4-(4-carboxy-2-(2-phenethyl)-phenoxymethyl)benzoate as (1.0 g, 2.3 mmol)in freshly distilled THF (12 ml) was treated with n-methyl morpholine(0.23 g, 2.3 mmol). The solution was cooled to -20° C. under argon andisobutyl chloroformate (0.32 g, 2.3 mmol) added keeping the temperaturebelow -20° C. The reaction was allowed to warm to -10° C. over 30minutes, then to -35° C. and treated with methylamine in methanol (1.3ml of 33% w/w solution, 10 mmol) keeping the temperature below -20° C.The reaction was then allowed to warm to ambient temperature, water wasadded and the reaction was extracted with ethyl ether (2×). The combinedetherial extracts were washed with brine, dried (MgSO₄) and evaporated.The product was purified by chromatography (ethyl acetate/ethyl ether)to give the title product as a white solid (0.33 g, 32%).

NMR (200 MHz, DMSO-d₆): δ8.2 (bm, 1H), 7.93 (d, 2H), 7.63 (m, 4H), 7.2(m, 6H), 5.27 (s, 2H), 2.88 (bs, 4H), 2.76 (d, 3H), 1.55 (s, 9H).

Reference Example 58 Preparation of methyl4-hydroxy-3-(2-phenethyl)benzoate

A suspension of 3-formyl-4-hydroxybenzoic acid (3.9 g, 23.5 mmol) in ofmethanol (50 ml) was cooled below 0° C. To the suspension was addedconcentrated H₂ SO₄ (3 ml) and the reaction was allowed to warm toambient temperature and stirred for 60 hours. The reaction was heated toreflux for 12 hours, the solvent evaporated and residue subjected tochromatography (eluant: ethyl ether/hexane) to give methyl3-formyl-4-hydroxybenzoate as a white solid (3.55 g, 84%).

NMR (200 MHz, DMSO-d₆): δ11.53 (s, 1H), 10.30 (s, 1H), 8.25 (d, 1H),8.06 (dd, lH), 7.10 (d, 1H), 3.84 (s, 3H).

To a solution of methyl 3-formyl-4-hydroxybenzoate (3.55 g, 19.7 mmol)in DMF (20 ml) was added benzyl bromide (3.70 g, 21.67 mmol) and K₂ CO₃(4.1 g, 29.6 mmol). The reaction was stirred at ambient temperatureovernight and the solvent evaporated to dryness (at reduced pressure).The residue was partitioned between ethyl ether and water and theaqueous layer extracted a second time with ethyl ether. The organicextracts were combined, washed with brine, dried (MgSO₄ ) and evaporatedto give methyl 3-formyl-4-benzyloxybenzoate as an off-white solid whichwas used without further purification.

NMR (200 MHz, DMSO-d₆): δ10.40 (s, 1H), 8.22 (m, 2H), 7.44 (m, 6H), 5.38(s, 2H), 3.85 (s, 3H).

To a stirred suspension of benzyl triphenylphosphonium bromide (8.96 g,20.6 mmol) in freshly distilled THF (80 ml) was added LiN(SiMe₃)₂ (1N inTHF, 23.6 ml). The resultant red solution was treated with a solution ofmethyl 4-benzyloxy-3-formylbenzoate, (5.5 g, 19.7 mmol) in THF (20 ml).The reaction was stirred at ambient temperature for 4 days, partitionedbetween ethyl ether and water and the water layer extracted with ethylether (2×). The combined organic extracts were washed with brine, dried(MgSO₄) and evaporated. The residue was purified by chromatography(eluant: ethyl ether/hexane) to give methyl4-benzyloxy-3-(2-phenethenyl)benzoate as a colourless solid (5.1 g,75%).

NMR (200 MHz, DMSO-d₆) (mixture of cis and trans isomers): δ8.24-6.6(series of complex multiplets, taken together 15H), 5.31 and 5.20 (twosinglets, together 2H) 3.85 and 3.72 (two singlets, together 3H).

To a solution of methyl 4-benzyloxy-3-(2-phenethenyl)-benzoate (0.5 g,1.45 mmol) in methanol (12 ml) was added 10% palladium on carbon (0.05g). The reaction was placed under an atmosphere of hydrogen and stirredvigorously until the uptake of hydrogen ceased, then filtered throughCelite and evaporated to give the title product as a colourless solid(0.37 g, quantitative).

NMR (200 MHz, DMSO-d₆): δ10.28 (s, 1H), 7.66 (m, 1H), 7.24 (m, 5H), 6.88(m, 1H), 3.66 (s, 3H), 2.83 (s, 4H).

Reference Example 59 Preparation of 4-acetyl-2-(2-phenethyl)phenol

To a stirred suspension of benzyl triphenylphosphonium bromide (7.44 g,17.2 mmol) in freshly distilled THF (60 ml), under argon, was added asolution of LiN(SiMe₃)₂ (18.2 ml, 1N). The resulting red solution wasallowed to stir for 30 minutes, then a solution of5-bromo-2-benzyloxybenzaldehyde (5.0 g, 17.2 mmol) in freshly distilledTHF (15 ml) added. The reaction was stirred at ambient temperature for60 hours, treated with 1N aqueous HCl (60 ml) and extracted with ethylether (2×). The combined etherial extracts were washed with brine, dried(MgSO₄) and evaporated. The residue was purified by chromatography(eluant:hexane) to give β-(2-benzyloxy-5-bromophenyl)styrene as a whitesolid (5.5 g, 88%).

NMR (250 MHz, DMSO-d₆) (mixture of cis and trans isomers): δ7.6-6.5(complex multiplets, taken together-15 H), 5.22 and 5.14 (two singlets,together, 2H).

To a solution of the above olefin (5.5 g, 15 mmol) in toluene (120 ml)and ethanol (120 ml) was added Wilkinson's catalyst (0.55 g). Thereaction mixture was hydrogenated at 50° C. and 50 Bar for 18 hours,then evaporated. The residue was purified by chromatography (eluant:ethyl ether/hexane) to give 4-benzyloxy-3-(phenethyl)phenylbromide as acolourless oil which slowly crystallized (5.5 g, quantitative).

NMR (200 MHz, DMSO-d₆): δ7.25 (m, 1H), 5.13 (s, 2H), 2.83 (brs, 4H).

To a stirred solution of the 4-benzyloxy-3-(phenethyl)phenylbromide,(5.5 g, 15 mmol) in DMF (200 ml, dried) was added CuCN (3.32 g, 37mmol). The reaction was heated to reflux and held at reflux for 20hours, under argon. The reaction mixture was allowed to cool to ambienttemperature, poured into ice water, treated with ethylene diamine (200ml) and extracted with ethyl acetate (3×100 ml). The combined organicextracts were washed with brine (2×60 ml), dried (MgSO₄) and evaporated.The crude material was purified by chromatography to give4-benzyloxy-3-phenethylbenzonitrile as a white solid (2.0 g, 43%).

NMR (250 MHz, DMSO-d₆): δ7.38 (m, 13H), 5.25 (s, 2H), 2.85 (m, 4H).

A solution of the cyano benzyl ether [from above] (1.0 g, 3.2 mmol) inethanol (100 ml) was treated with 10% palladium on carbon. The reactionwas placed under an atmosphere of hydrogen, stirred until the uptake ofhydrogen ceased, filtered through celite and evaporated. The product waspurified by chromatography (eluant: ethyl acetate/hexane) to give4-cyano-2-(2-phenethyl)phenol as a white solid (0.64 g, 90%).

NMR (250 MHz, DMSO-d₆): δ10.58 (s, 1H), 7.47 (m, 2H), 7.23 (m, 5H), 6.95(d, 1H), 2.83 (s, 4H).

A solution of 4-cyano-2-(2-phenethyl)phenol (0.64 g, 2.87 mmol) in THF(25 ml) under argon was cooled to -65° C. To the solution was added,over 10 minutes, a solution of methyl lithium (1.4M in ethyl ether, 5ml). The resultant reaction was allowed to warm to ambient temperatureover 3 hours, treated with water and dilute aqueous HCl to approx pH 1.The reaction was extracted with ethyl acetate (2×), the combinedextracts washed with brine, dried (MgSO₄) and evaporated and the residuepurified by chromatography (eluant: ethyl acetate/hexane) to give thetitle product as an off-white solid (0.5 g, 72%).

NMR (250 MHz, CDCl₃): δ7.45 (m, 2H), 7.26 (m, 5H), 6.80 (m, 1H), 5.68(s, 1H), 2.94 (s, 4H), 2.50 (s, 3H).

Reference Example 60

Not used.

Reference Example 61

Not used.

Reference Example 62

Not used.

Reference Example 63 Preparation of methyl4-[6-methanesulphonyl-2-(2-phenethyl)phenoxymethyl]benzoate

A solution of methyl4-[6-methylthio-2-(2-phenethyl)-phenoxymethyl]benzoate (0.38 g, 0.97mmol) in dry CH₂ Cl₂ (10 ml) was cooled to 0° C. To the cooled reactionwas added a solution of m-CPBA (0.609 g, 55%, 1.94 mmol in 10 ml CH₂ Cl₂), keeping the temperature below 2° C. The reaction mixture was stirredat 0° C. for 20 minutes and then allowed to warm to ambient temperatureover 30 minutes. The reaction mixture was washed twice with saturatedNaHCO₃ and the organic layer dried (MgSO₄) and evaporated.

NMR: (200 MHz, DMSO-d₆) δ2.95 (m, 4H), 3.25 (s, 3H), 3.88 (s, 3H), 5.1(s, 2H), 7.15 (m, 5H), 7.39 (t, 1H), 7.63 (d, 2H), 7.75 (d, 2H), 8.03(d, 2H).

Reference Example 64 Preparation of methyl4-[4-benzenesulphonylmethyl-2-(2-phenethyl)phenoxymethyl]benzoate

A solution of the methyl4-[4-phenylthiomethyl-2-(2-phenethyl)phenoxymethyl]benzoate (0.43 g,0.92 mmoles) in CH₂ Cl₂ (5 ml) was cooled to 0° C. To this cooledsolution was added portionwise, over 10 minutes, m-CPBA (0.58 g, [55%],1.84 mmoles). The reaction was stirred at 0° C. for 1.75 hours. Thereaction mixture was diluted with CH₂ Cl₂ and washed twice withsaturated NaHCO₃.

The organic phase was dried (MgSO₄) and evaporated. The residue waspurified by chromatography (diethyl ether/hexane) to give the titleproduct (0.33 g, 72%).

NMR (200 MHz, DMSO-d₆): δ2.71 (m, 4H), 3.86 (s, 3H), 4.54 (s, 2H), 5.18(s, 2H), 6.89 (bs, 1H), 6.96 (bs, 2H), 7.18 (m, 5H), 7.64 (m, 7H), 7.98(d, 2H)

Reference Example 65

Not used.

Reference Example 66 Preparation of tert-butyl4-[6-methanesulphonylmethyl-2-(2-phenethyl)phenoxymethyl]benzoate andtert-butyl4-[6-methanesulphinylmethyl-2-(2-phenethyl)-phenoxymethyl]benzoate

To a cooled (0° C.) stirred solution of tert-butyl4-[6-methylthiomethyl-2-(2-phenethyl)phenoxymethyl]benzoate (0.81, 1.8mmol), in CH₂ Cl₂ (30 ml) was added m-CPBA (1.13 g, (53%) 3.62 mmole)portionwise over 15 minutes. The reaction was stirred at 0° C. for 30minutes and then allowed to warm to ambient temperature. The reactionwas diluted with CH₂ Cl₂ and washed with saturated NaHCO₃. The organicphase was dried (MgSO₄) and evaporated and the residue was purified bychromatography (MeOH/CH₂ Cl₂) to give the title products: tert-butyl4-[6-methanesulphonylmethyl-2-(2-phenethyl)phenoxymethyl]benzoate (0.120g, 14%) MS (CI⁺): 478 [M+NH₄ ]⁺ and tert butyl4-[6-methanesulphinylmethyl-2-(2-phenethyl)phenoxymethyl]benzoate (0.48g, 60%) MS(CI⁺): 465 [M+H]⁺.

Reference Example 67 Preparation of methyl3-(6-isopropyl-2-(2-phenethyl)phenoxymethyl)-benzoate

A solution of 6-isopropyl-2-(2-phenethyl)phenol (2.5 g, 19.42 mmol) inDMF (15 mL) was treated with K₂ CO₃ (2.875 g, 20.83 mmol) and methyl3-bromomethylbenzoate (2.62 g, 11.44 mmol). The reaction was stirred atambient temperature overnight and then partitioned between ethylacetate/H₂ O. The organic phase was washed with H₂ O(x4), dried (MgSO₄)and evaporated. The residue was purified by chromatography (eluant:diethyl ether/hexane) to give methyl3-(6-isopropyl-2-(2-phenethyl)phenoxy-methyl)benzoate (3.3 g, 82%).

NMR: (200 MH₂, DMSO-d₆): δ8.11 (m, 1H), 7.96 (m, 1H), 7.74 (m, 1H), 7.57(t, 1H), 7.15 (m, 8H), 4.87 (s, 2H), 3.87 (s, 3H), 3.30 (m, 1H), 2.86(s, 4H), 1.19 (d, 6H).

Reference Example 68

Using a similar method to that of Reference Example 67, the compounds ofTable XIV were prepared.

                  TABLE XIV                                                       ______________________________________                                        4  STR92##                                                                       -      Equivalents                                                            of bromo Equivalents                                                         R Compound of K.sub.2 CO.sub.3 MS Footnotes                                 ______________________________________                                        6-Br  1.0       2.0        CI.sup.+ : 425 (M + H)+                                                                  a                                         4-Br 1.1 1.3 -- b                                                             4-OCH.sub.3 1.1 1.3 -- b                                                    ______________________________________                                         Footnotes                                                                     a Reaction mixture filtered and evaporated and the residue purified by        subjecting to chromatography, eluting with diethyl ether/hexane.              b Reaction mixture evaporated and residue partitioned between ethyl           acetate and water and organic phase evaporated. Product used in subsequen     step without further purification.                                       

Reference Example 69 Preparation of tert-butyl4-(6-N-methylcarbamoyl-2-(2-phenethyl)phenoxymethyl)benzoate

A solution of tert butyl4-(6-methoxycarbonyl-2-(2-phenethyl)phenoxymethyl)benzoate (0.42 g, 0.94mmol) in methylamine (15 ml, 33% w/w in industrial methylated spirits)was placed in a carius tube and heated at 100° C. for 12 hours. Thereaction mixture was evaporated. The residue was purified bychromatography (dichloromethane, methanol) to give the desired product(0.29 g, 70%). MS (FAB+): 446 (M+H)⁺. The starting material was preparedaccording to Reference example 7 Table XVII compound 1.

Reference Example 70 Preparation of 3-chloro-2-hydroxybenzaldehyde

a) A suspension of 3-chlorosalicylic acid (1.5 g, 8.7 mmol) indichloromethane (10 ml) was treated with oxalyl chloride (1.59 g, 13mmol) and 1 drop of DMF. The reaction was stirred at ambient temperaturefor 2 hours, evaporated to dryness and used immediately in the nextstep.

b) 3-Chloro-2-hydroxybenzoylchloride (8.7 mmol) was dissolved in diglyme(10 ml) and cooled to -70° C. under argon. Lithiumtritertbutoxyaluminohydride (0.5M, 34.8 ml 17.4 mmol) was added viasyringe keeping the temperature below -60° C. The reaction was stirredat -60° C. for 2% hours. The reaction mixture was poured onto ice,acidified with concentrated HCl and extracted with ethyl acetate (2×).The organic phases were combined, dried over MgSO₄ and evaporated. Flashchromatography (eluant: CH₂ Cl₂ /hexanes) gave the title product (0.2 g,1.3 mmol). MS (CI⁺) (M+NH₄)⁺ 174

What is claimed is:
 1. A compound of the formula (I): ##STR93## wherein: A is an 8-, 9- or 10-membered bicyclic heteroaryl, a 5- or 6-membered heteroaryl, naphthyl or phenyl, or any of the foregoing substituted with E where E is selected from the group consisting of C₁ -C₆ -alkyl, mono- or di-substituted C₁ --C₆ -alkyl (where the substituent is independently selected from hydroxy, amino, halo, nitro, C₁ -C₄ -alkyl-S(O)_(p) -, C₁ -C₄ -alkoxy, phenyl-S(O)_(p) -, or cyano), halo, trifluoromethyl, nitro, hydroxy, amino, C₁ -C₄ -alkylamino, di-C₁ -C₄ -alkylamino, cyano, C₁ C₆ -alkoxy, C₁ -C₆ -alkyl-S(O)_(p) -, phenyl-S(O)_(p) -, carbamoyl, C₂ -C₆ -alkenyl, C₂ -C₆ -alkynyl, C₃ -C₇ -cycloalkyl, C₃ -C₇ -cycloalkyl-C₁ -C₃ -alkyl, C₃ -C₇ -cycloalkyl-C₂ -C₃ -alkenyl, C₃ -C₇ -cycloalkyl-C₂ -C₃ -alkynyl, C₁ -C4-alkoxycarbonylamino, C₁ -C4-alkanoylamino, C₁ -C4-alkanoyl-(N-C₁ -C₄ -alkyl)amino, C₁ -C4-alkanesulphonamido, benzenesulphonamido, aminosulphonyl, C₁ -C₄ -alkylaminosulphonyl, di-C₁ C₄ -alkyl-aminosulphonyl, C₁ -C₄ -alkoxycarbonyl, C₂ -C₄ -alkanoyloxy, formyl-C₁ -C₄ -alkyl, trifluoro-C₁ -C₃ -alkylsulphonyl, hydroxyimino-C₁ -C₆ -alkyl, C₁ -C₄ -alkoxyimino-C₁ -C₆ -alkyl, C₁ -C₆ -alkylcarbamoylamino, phenyl, C₁ -C₄ -alkylcarbamoyl and di-C₁ -C₄ -alkyl-carbamoyl; provided that if A is a ring structure, the --OCH(R³)- and -X- linking groups are positioned in a 1,2 relationship to one another on ring carbon atoms of A, wherein p is 0, 1 or 2;B is phenyl or a 5- or 6-membered heteroaryl ring, or either of the foregoing substituted with G, where G is selected from the group consisting of halo, trifluoromethyl, nitro, hydroxy, C₁ -C₆ -alkyl, C₃ -C₇ -cycloalkyl, C₃ -C₇ -cycloalkyl-C₁ -C₃ -alkyl, amino, C₁ -C₄ -alkylamino, di-C₁ -C₄ -alkyl-amino, cyano, -S(O)_(p) -C₁ -C₆ -alkyl, carbamoyl, C₁ -C₄ -alkylcarbamoyl and di-C₁ -C₄ -alkyl-carbamoyl; D is pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, thienyl, furyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl or phenyl, or any of the foregoing mono- or di-substituted with halo, trifluoromethyl, nitro, hydroxy, amino, C₁ -C₄ -alkylamino, di-C₁ -C₄ -alkyl-amino, cyano, C₁ -C₆ -alkoxy, --S(O)_(p) -C₁ -C₄ -alkyl, --S(O)_(p) -phenyl, C ₁ -C₄ -alkanoyl, C₁ -C₄ -alkyl or C₁ -C₄ -alkyl mono-substituted with hydroxy, halo, nitro, cyano or amino; R¹ is carboxy, carboxy-C₁ -C₃ -alkyl, tetrazolyl, tetrazolyl-C₁ -C₃ -alkyl, tetronic acid, hydroxamic acid, sulphonic acid, or R¹ is of the formula -CONR^(a) R^(a1) :where R^(a) is hydrogen or C₁ -C₆ -alkyl, and R^(a1) is J or hydrogen, where J is selected from C₁ -C₆ -alkyl, C₂ -C₆ -alkenyl, C₂ -C₆ -alkynyl, C₃ -C₇ -cycloalkyl, C₃ -C₇ -cycloalkyl-C₁ -C₆ -alkyl, C₃ -C₇ -cycloalkyl-C₂ -C₆ -alkenyl, C₃ -C₇ -cycloalkyl-C₂ -C₆ -alkynyl, C₅ -C₇ -cycloalkenyl, C₅ -C₇ -cycloalkenyl-C₁ -C₆ -alkyl, C₅ -C₇ -cycloalkenyl-C₂ -C₆ -alkenyl, C₅ -C₇ -cycloalkenyl-C₂ -C₆ -alkynyl, or R^(a1) is J mono-substituted with a 5- or 6-membered saturated or partially-saturated heterocyclic ring, a 5- or 6-membered heteroaryl ring or a 5- or 6-membered heteroaryl-C₁ -C₃ -alkyl; or where R^(a) and R^(a1) together with the nitrogen to which they are attached form a group having the formula --NH--CH(R^(C))--COOR^(D) wherein R^(C) is hydrogen, C₁ -C₆ -alkyl, C₂ -C₆ -alkenyl, C₂ -C₆ -alkynyl, phenyl, phenyl(C₁ -C₃ -alkyl), 5- or 6-membered heteroaryl or 5- or 6-membered heteroaryl(C₁ -C₃ -alkyl) and R^(D) is H or C₁ -C₆ -alkyl, wherein any alkyl, alkenyl, alkynyl, phenyl or heteroaryl group of the foregoing is either unsubstituted or mono- substituted with E; R¹ is of the formula --CONHSO₂ J; X is of the formula --(CHR⁴)_(n) -- or --(CHR⁴)_(r) CR⁴ ═CR⁴ (CHR⁴)_(q) --, where n is 1, 2 or 3; and r and q are either both 0, or r is 0 and q is 1, or r is 1 and q is 0; andR³ and R⁴ are independently selected from hydrogen or C₁ -C₄ -alkyl; wherein: when B is a 6-membered ring, R¹ is positioned on ring B in a 1,3 or a 1,4 relationship with the --OCH(R³)-- linking group, or when B is a 5-membered ring, R¹ is positioned in a 1,3 relationship with the --OCH(R³)-- linking group; or an N-oxide of any of the foregoing compounds; or any of the foregoing compounds having S-oxides of sulphur containing rings therein; or a pharmaceutically-acceptable salt or an in vivo hydrolysable ester or amide of any of the foregoing compounds; provided the compound of formula (I) is not 4-(2-benzyl-3-hydroxy-4-formylphenoxymethyl)-3-methoxybenzoic acid, or 4-(2-(3-phenylprop-2-en-1-yl)-3-hydroxy-4-formylphenoxymethyl)-3-methoxybenzoic acid.
 2. A compound according to claim 1, wherein A is phenyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, thienyl or 1,2,3-thiadiazolyl or any of the foregoing mono- or di-substituted with E.
 3. A compound according to claim 1, wherein B is phenyl, pyridyl, thiazolyl, thienyl, thiadiazolyl, pyrazinyl, pyridazinyl or pyrimidyl or any of the foregoing mono- or di-substituted with G.
 4. A compound according to claim 1, wherein D is phenyl or phenyl mono- or di-substituted with halo, trifluoromethyl, nitro, hydroxy, amino, C₁ C₄ -alkylamino, di-C₁ -C₄ -alkylamino, cyano, C₁ C₆ -alkoxy, -S(O)_(p) -C₁ -C₄ -alkyl, -S(O)_(p) -phenyl, C₁ -C₄ -alkanoyl, C₁ -C₄ -alkyl or C₁ -C₄ -alkyl mono- or di-substituted with hydroxy, halo, nitro, cyano or amino.
 5. A compound according to claim 1, having the formula (V). ##STR94## wherein: X is --(CH₂)₂ -- or --CH═CH--;B is phenyl, thiadiazolyl or pyridyl; and R⁶ is hydrogen, halo, trifluoromethyl, nitro, hydroxy, amino, cyano, C₁ -C₆ -alkoxy, C₁ -C₆ -alkyl-S(O)_(p), phenyl-S(O)_(p), C₁ -C₆ -alkyl mono- or di-substituted by hydroxy, amino, halo, nitro or cyano, C₃ -C₇ -cycloalkyl, C₃ -C₇ -cycloalkyl-C₁ -C₃ -alkyl, carbamoyl, C₁ -C₄ -alkylcarbamoyl, di-C₁ -C₄ -alkyl-carbamoyl, C₂ -C₆ -alkenyl, C₂ -C₆ -alkynyl, C₁ -C₄ -alkoxycarbonylamino, C₁ -C₄ -alkanoylamino, C₁ -C₄ -alkanoyl(N-C₁ -C₄ -alkyl)amino, C₁ -C₄ -alkanesulphonamido, benzenesulphonamido, aminosulphonyl, C₁ -C₄ -alkylaminosulphonyl, di-C₁ -C₄ -alkyl-aminosulphonyl, C₁ -C₄ -alkoxycarbonyl, C₂ -C₄ -alkanoyloxy, C₁ -C₆ -alkanoyl, formyl-C₁ -C₄ -alkyl, trifluoro-C₁ -C₃ -alkylsulphonyl, hydroxyimino-C₁ -C₆ -alkyl, C₁ -C₄ -alkoxyimino-C₁ -C₆ -alkyl or C₁ -C₆ -alkylcarbamoylamino.
 6. A compound according to claim 1, selected from the group consisting of:4-[6-bromo-2-(phenethyl)phenoxymethyl]benzoic acid; 4-[5-nitro-2-(phenethyl)phenoxymethyl]benzoic acid; 4-[4-chloro-6-methyl-2-(phenethyl)phenoxymethyl]benzoic acid; 4-[5-bromo-6-cyano-2-(phenethyl)phenoxymethyl]benzoic acid; 4-[5-chloro-2-(phenethyl)phenoxymethyl]benzoic acid; 4-[4-cyanomethyl-2-(phenethyl)phenoxymethyl]benzoic acid; 4-[2-(phenethyl)phenoxymethyl]benzoic acid; 4-[6-bromo-2-(phenethyl)phenoxymethyl]-2-hydroxybenzoic acid; 4-[5-methyl-2-(phenethyl)phenoxymethyl]benzoic acid; 4-[2-(phenethyl)-6-phenylphenoxymethyl]benzoic acid; 4- [6-amino-2-(phenethyl)phenoxymethyl]benzoic acid; 4- [6-methanethio-2-(phenethyl )phenoxymethyl]benzoic acid; 4-[4-(1-(hydroxyimino)ethyl)-2-(phenethyl)phenoxymethyl]benzoic acid; 4-[4-methyl-2-(phenethyl)phenoxymethyl]benzoic acid; 4-[4-bromo-2-(phenethyl)phenoxymethyl]benzoic acid; 4-[4-methoxy-2-(phenethyl)phenoxymethyl]benzoic acid; 4-[6-cyano-2-(phenethyl)phenoxymethyl]benzoic acid; 4-[6-cyano-4-methyl-2-(phenethyl)phenoxymethyl]benzoic acid; 4-[4-chloro-2-(phenethyl)phenoxymethyl]benzoic acid; 4-[6-benzenesulphonylmethyl-2-(phenethyl)phenoxymethyl]benzoic acid; 4-[4-methanethio-2-(phenethyl)phenoxymethyl]benzoic acid; 4-[5-bromo-2-(phenethyl)phenoxymethyl]benzoic acid; 4-[6-isopropyl-2-(phenethyl)phenoxymethyl]benzoic acid; 5- [4-(2-(phenethyl)-6-phenylphenoxymethyl)phenyl]tetrazole; 5- [4-(4-hydroxy-2-(phenethyl)phenoxymethyl)phenyl]tetrazole; 5-[4-(4-methoxy-2-(phenethyl)phenoxymethyl)phenyl]tetrazole; 5- [4-(2-(phenethyl)phenoxymethyl)phenyl]tetrazole; 5- [4-(4-chloro-2-(phenethyl)phenoxymethyl)phenyl]tetrazole; 5-[4-(4-bromo-2-(phenethyl)phenoxymethyl)phenyl]tetrazole; 5-[4-(6-bromo-2-(phenethyl)phenoxymethyl)phenyl]tetrazole; and 5-[4-(6-isopropyl-2-(phenethyl)phenoxymethyl)phenyl]tetrazole, ora pharmaceutically-acceptable salt or an in vivo hydrolysable ester or amide of any of the foregoing compounds.
 7. A pharmaceutical composition which comprises a compound according to claim 1 and a pharmaceutically-acceptable excipient or diluent.
 8. A method of relieving pain in a patient suffering therefrom, said method comprising administering a therapeutically effective amount of compound according to claim
 1. 9. A process for preparing a compound of formula (I) according to claim 1, said process comprising:ia) when X is --(CHR⁴)_(n) --, and n is 2 or 3, reducing a compound of formula: ##STR95## ib) when X is -(CHR⁴)_(n) - and n is 1, 2 or 3, reacting a compound of formula: ##STR96## with a compound of formula:

    L--CH(R.sup.3)--B--R.sup.1

wherein L is a leaving group; or ic) when A is an activated heterocyclic ring, reacting a compound of formula: ##STR97## with a compound of formula: ##STR98## where, in any of the foregoing steps, ia), ib) or ic), any of A, B, D, X, R¹, R³ and R⁴ bear protective groups when necessary; ii) removing any of said protecting groups; and iii) forming a pharmaceutically-acceptable salt of any of the foregoing compounds.
 10. A process according to step ia), ib) or ic) of claim 9, for preparing a compound having the formula (V): ##STR99## 